Research trends of ferroptosis and pyroptosis in depression: A bibliometric analysis

Abstract

BACKGROUND

Depression is a major psychiatric disorder with substantial clinical and social burdens. Ferroptosis and pyroptosis/inflammasome-related signaling have emerged as potential mechanisms involved in depression; however, their research landscapes, hotspots, and developmental trends have not been comprehensively characterized.

AIM

To investigate global research trends, collaboration patterns, knowledge structure, and emerging hotspots of ferroptosis- and pyroptosis-related research in depression using bibliometric methods.

METHODS

Relevant publications through June 2, 2026 were retrieved from the Web of Science Core Collection, and bibliometric analyses were performed using VOSviewer and CiteSpace.

RESULTS

Publications on pyroptosis in depression emerged earlier and increased steadily, whereas research on ferroptosis in depression began later but expanded rapidly in recent years. China and the United States were the leading contributors to both research areas, although ferroptosis-related publications showed a greater concentration in China. International Journal of Molecular Sciences was the most productive journal in the ferroptosis dataset, while International Immunopharmacology led the pyroptosis dataset. Keyword analysis highlighted oxidative stress, iron metabolism, lipid peroxidation, neuroinflammation, NOD-like receptor family pyrin domain-containing 3 inflammasome signaling, microglial activation, and pathway-targeted interventions as major research themes. Although the 2 fields shared several pathological contexts, publications directly investigating their interactions in depression were relatively scarce.

CONCLUSION

Ferroptosis and pyroptosis have become increasingly important topics in depression research, with ferroptosis representing a particularly rapidly developing area. Current studies largely focus on oxidative and inflammatory mechanisms and their potential therapeutic targets. However, the limited integration of ferroptosis and pyroptosis research indicates a need for further studies examining their potential crosstalk and coordinated contribution to the pathophysiology of depression.

Key Words: Depression; Ferroptosis; Pyroptosis; Bibliometric analysis; CiteSpace; VOSviewer

Core Tip: This bibliometric analysis maps the global research landscape of ferroptosis- and pyroptosis-related mechanisms in depression. Pyroptosis-related research emerged earlier, whereas ferroptosis-related research has increased rapidly in recent years. Oxidative stress, neuroinflammation, iron metabolism, mitochondrial dysfunction, and targeted interventions are major themes. The findings identify leading contributors, evolving hotspots, and the need for integrated mechanistic and clinical studies to evaluate regulated cell death pathways as potential biomarkers and therapeutic targets for depression.

INTRODUCTION

Depression is a psychiatric disorder characterized primarily by persistent low mood, diminished interest, and anhedonia and is frequently accompanied by cognitive impairment, sleep disturbances, and an increased risk of suicide[1]. According to the latest Global Burden of Disease data published in The Lancet, depressive disorders ranked second in years lived with disability from 2010 to 2021, with the disease burden continuing to rise and imposing substantial economic and psychological burdens on patients, families, and society[2]. However, despite its considerable disease burden, current first-line antidepressants have important limitations, including delayed onset of action, low response rates, and significant adverse effects. Moreover, the pathogenesis of depression remains incompletely understood, which represents not only a major bottleneck in clinical treatment but also a central focus of basic research[3].

Traditionally, research on the pathophysiological mechanisms of depression has primarily focused on theories involving monoaminergic neurotransmitter dysfunction, neuroendocrine abnormalities, and deficiencies in neurotrophic factors[4]. However, the neuroinflammation hypothesis of depression has gained increasing attention[5]. Accumulating evidence indicates that patients with depression exhibit significantly elevated levels of pro-inflammatory cytokines in both peripheral blood and the central nervous system, while chronic stress can activate microglia in the brain, trigger inflammatory cascades, and subsequently impair neuronal function and synaptic plasticity[6]. Nevertheless, the upstream drivers and downstream effector mechanisms of neuroinflammation remain incompletely understood. In recent years, dysregulated programmed cell death (PCD) has been increasingly recognized as being closely associated with the onset and progression of depression. Multiple PCD pathways, including apoptosis, autophagy, ferroptosis, and pyroptosis, have been shown to play critical roles in the pathological process of depression[7]. These findings not only provide a new cellular-level perspective for understanding the pathogenesis of depression but also open new avenues for the development of therapeutic strategies targeting novel cell death pathways.

Ferroptosis, first defined in 2012, is a form of iron-dependent PCD characterized primarily by excessive intracellular iron accumulation and the buildup of lipid peroxidation products, ultimately leading to disruption of membrane integrity and cell death[8]. Unlike apoptosis, ferroptosis is morphologically characterized by mitochondrial shrinkage, reduced cristae, and increased membrane density, while biochemically it is driven by inactivation of the glutathione peroxidase 4 (GPX4) system and acyl-CoA synthetase long-chain family member 4–mediated lipid peroxidation[9]. In recent years, the relationship between ferroptosis and depression has attracted increasing attention. Studies have shown that patients with depression exhibit elevated iron levels, reduced glutathione content, and increased production of malondialdehyde and reactive oxygen species (ROS) in brain tissue, suggesting aberrant activation of the ferroptosis pathway during the pathological process underlying depressive-like behaviors[10]. In animal models of depression induced by chronic social defeat stress, GPX4 expression in the hippocampus is downregulated, whereas acyl-CoA synthetase long-chain family member 4 expression is upregulated, and targeted inhibition of ferroptosis has been shown to significantly ameliorate depressive-like behaviors[11]. Mechanistically, lipid peroxidation damage mediated by Fenton reactions triggered by disordered iron metabolism not only directly compromises neuronal membrane integrity but also further amplifies the vicious cycle between oxidative stress and mitochondrial dysfunction, thereby forming a pathogenic “ferroptosis-mitochondria axis”[12]. Collectively, these findings indicate that ferroptosis plays a crucial role in the pathophysiological progression of depression and may represent a highly promising therapeutic target.

Another form of PCD that has attracted increasing attention alongside ferroptosis is pyroptosis. Pyroptosis is a pro-inflammatory mode of cell death mediated by inflammasome activation and is characterized molecularly by the assembly of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, activation of caspase-1, and gasdermin D-mediated membrane pore formation, ultimately resulting in the extracellular release of large amounts of pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18, and triggering robust inflammatory responses[13]. In the pathological context of depression, chronic social defeat stress can induce excessive activation of the NLRP3 inflammasome in microglia, thereby initiating the pyroptotic cascade. This process not only directly damages neurons and synaptic structures but also promotes the release of large quantities of inflammatory mediators, impairs neurogenesis and synaptic plasticity, and drives dysfunction in emotion-related brain regions such as the prefrontal cortex and hippocampus[14]. The classical microglial pyroptosis pathway, namely the NLRP3/caspase-1/gasdermin D axis, is significantly activated in depression models, and inhibition of its aberrant activation can effectively alleviate depressive-like behavior[14]. In addition, a novel mechanism whereby 5-lipoxygenase induces depressive-like behaviors through activation of NLRP3-mediated pyroptosis has gradually been elucidated, suggesting that modulation of the pyroptosis pathway may represent a promising new strategy for antidepressant therapy[15].

Notably, although ferroptosis and pyroptosis are classified as distinct forms of PCD, they are not isolated pathological events but rather exhibit complex interactions and synergistic effects. Emerging evidence suggests that both ferroptosis and pyroptosis contribute to depression and cognitive decline and are closely associated with reduced levels of brain-derived neurotrophic factor[16]. More importantly, there is substantial crosstalk between the signaling pathways of ferroptosis and pyroptosis: Oxidative stress serves not only as a core driver of ferroptosis but also as a key upstream signal for NLRP3 inflammasome activation, while mitochondrial dysfunction is involved in the pathogenesis of both processes[17]. Although the interplay between ferroptosis and pyroptosis has been reported in tumors, their interactive mechanisms in neurological disorders, particularly depression, remain insufficiently studied[18]. This gap highlights the importance of integrating ferroptosis and pyroptosis into a unified analytical framework to achieve a more comprehensive understanding of the cell death-related pathological mechanisms underlying depression.

In recent years, bibliometrics, as a research tool that quantitatively analyzes scientific literature using mathematical and statistical methods, has been widely applied in the biomedical field to assess research landscapes, identify emerging hotspots, and predict future trends. Bibliometric analysis can systematically reveal the knowledge structure, developmental trajectory, and collaboration networks of a given research field, thereby providing researchers with intuitive and reliable quantitative evidence for tracking disciplinary dynamics and recognizing emerging directions[19]. In the field of depression research, bibliometric methods have already been used to analyze multiple topics, including the roles of microglia and astrocytes in depression, as well as the association between the gut microbiota and depression[20]. However, bibliometric analysis of the intersecting fields of ferroptosis and pyroptosis in depression remains lacking. At present, studies on ferroptosis and pyroptosis in depression have mainly focused on molecular mechanisms and experimental interventions, while a systematic visualized bibliometric investigation of the current research status, shifting hotspots, core research forces, and future developmental trends in this field is still absent.

Based on the aforementioned research background, this study employed bibliometric methods to systematically retrieve literature data related to depression, ferroptosis, and pyroptosis from the Web of Science Core Collection (WoSCC). Using visualization tools such as CiteSpace and VOSviewer, we constructed a knowledge map of this field to reveal research hotspots and emerging trends, identify key research institutions and authors, and elucidate the historical evolution and future directions of this interdisciplinary field. This study not only provides a systematic integration of literature evidence for research on the mechanisms of cell death in depression but also offers valuable reference material for researchers and policymakers in related fields.

MATERIALS AND METHODS

Data source

All data were obtained from the Science Citation Index Expanded of the WoSCC database. The following search strategy was used: #1 TS = depression*, #2 TS = ferropto*, and #3 TS = pyropto* OR inflammasome. Searches were then conducted using #1 AND #2 and #1 AND #3, respectively. The search was completed on June 2, 2026. The methodology for data retrieval and collection is shown in Figure 1. The retrieved records were exported in plain text format, including full records and cited references, and saved as “download_txt” files.

Figure 1 Flow diagram of document identification, screening, and inclusion for the ferroptosis-related and pyroptosis-related depression datasets retrieved from the Web of Science Core Collection. The diagram shows the search strategies, record-selection procedures, eligibility criteria, reasons for exclusion, and final datasets included in the bibliometric analyses. Separate screening pathways are shown for the ferroptosis-related and pyroptosis-related datasets. For the pyroptosis-related dataset, studies addressing inflammasome activation without evidence of pyroptotic cell death or pyroptosis-related execution mechanisms were excluded. SCIE: Science Citation Index Expanded; SSCI: Social Sciences Citation Index; TS: Topic search; WoSCC: Web of Science Core Collection.

Two investigators independently screened the titles and abstracts of records retrieved for the pyroptosis dataset. Studies addressing inflammasome activation alone, without evidence of pyroptotic cell death or discussion of pyroptosis-related execution mechanisms (e.g., gasdermin-mediated membrane pore formation, cell membrane rupture, or pyroptosis-related cell lysis), were excluded. Discrepancies were resolved through discussion with a third investigator.

Statistical analysis

Bibliometric and visual analyses were performed using VOSviewer 1.6.19 and CiteSpace 6.2.R5. VOSviewer focuses primarily on the graphical representation of bibliometric networks and was used to visualize collaborations among countries/regions, institutions, authors, and journals, as well as author co-citation, journal and reference co-citation, and keyword co-occurrence. CiteSpace, which is more specialized in detecting emerging trends and extracting forward-looking information from the literature, was used for burst detection of references, dual-map overlay analysis of journals, keyword clustering analysis, and timeline analysis.

RESULTS

Annual publication volume and trend analysis

The annual number of publications reflects the research trends in a given field. As shown in Figure 2, publications in the broader pyroptosis/inflammasome-related depression dataset appeared earlier than ferroptosis-related publications. The earliest retrieved record was published in 2010 and discussed the P2X purinoceptor 7 receptor as a potential mediator of inflammatory responses in psychiatric and neurological disorders. However, this article should be interpreted as part of the early P2X purinoceptor 7 receptor- and inflammation-related literature rather than as direct evidence of pyroptosis in depression. A more authoritative early reference linking psychological stress, depression, and inflammasome signaling was published by Iwata et al[21] in 2013. This review provided an important conceptual framework for subsequent research on inflammasome-related mechanisms in depression.

Figure 2 Annual publication output and cumulative growth trends in ferroptosis- and pyroptosis-related depression research. The bar charts illustrate annual publication trends in the 2 research fields, while the line graphs depict the cumulative number of publications.

The first study on “ferroptosis in depression” was published in 2019. This study investigated the effects of pre-lesioning noradrenergic neurons in the locus coeruleus in acetaminophen- and paraquat-induced Parkinson’s disease mouse models, revealing that injury to these neurons significantly aggravated depressive-like behavior and memory impairment. It further demonstrated that learning and memory deficits were mediated by enhanced ferroptosis and microglial M1 polarization, thereby highlighting the potential contribution of locus coeruleus neuronal damage to depression[22].

Subsequently, studies in both fields gradually began to emerge. Before 2015, publication output in both fields was very low, indicating that research on ferroptosis and pyroptosis in depression was still at an early stage. From 2015 to 2026, pyroptosis-related publications increased gradually and steadily. By contrast, ferroptosis-related publications grew rapidly after 2022, indicating increasing research attention.

Country/region analysis

A total of 21 and 61 countries/regions participated in research on “ferroptosis in depression” and “pyroptosis in depression”, respectively. Table 1 summarizes the top 10 most productive countries/regions in these 2 fields. China and the United States ranked first and second, respectively, in both publication output and citation counts. Their outputs exceeded those of other countries, indicating their prominent positions in the analyzed literature. As shown in Figure 3A and B, publications in both fields were mainly concentrated in East Asia, North America, and Oceania. According to the international collaboration networks, China showed the highest total link strength (TLS) in the field of “ferroptosis in depression” (Figure 3C), whereas the United States exhibited the highest TLS in the field of “pyroptosis in depression” (Figure 3D). These findings indicate their relatively prominent roles in international collaboration.

Figure 3 Geographic distribution and international collaboration networks of countries/regions in ferroptosis- and pyroptosis-related depression research. A: Geographic distribution of publications on ferroptosis in depression; B: Geographic distribution of publications on pyroptosis in depression; C: International collaboration network of countries/regions in ferroptosis in depression; D: International collaboration network of countries/regions in pyroptosis in depression. In these visual maps, each node represents a country, and the links between countries represent collaborative relationships. The size of each node is proportional to the total number of publications. Red nodes indicate greater collaboration between a country and other countries, while thicker connecting lines between nodes indicate closer collaboration between the 2 countries.

Table 1 Top 10 countries with the most publications on ferroptosis and pyroptosis in depression.

Type	Rank	Country	Documents	Citations	Total link strength
Ferroptosis in depression	1	China	139	3157	21
	2	United States	12	722	14
	3	Germany	3	144	1
	4	Australia	2	6	7
	5	South Korea	2	18	2
	6	Malaysia	2	41	1
	7	Egypt	2	10	0
	8	Brazil	1	6	6
	9	Bulgaria	1	6	6
	10	Cameroon	1	6	6
Pyroptosis in depression	1	China	579	20211	58
	2	United States	96	11770	74
	3	Italy	30	4106	27
	4	India	28	533	12
	5	Canada	25	1455	21
	6	Brazil	25	1188	13
	7	England	22	1064	30
	8	Australia	20	1320	25
	9	Germany	20	1364	17
	10	Spain	19	1145	20

Institutional analysis

A total of 271 and 1185 institutions participated in research on “ferroptosis in depression” and “pyroptosis in depression,” respectively, the vast majority of which were comprehensive universities and medical universities. The top 10 most productive institutions in these 2 fields are listed in Table 2. In the field of “ferroptosis in depression,” 9 of the top 10 institutions were from China, and Guangzhou University of Chinese Medicine ranked first in both the number of publications and TLS. Similarly, in the pyroptosis dataset, 9 of the 10 most productive institutions were located in China. Nanjing University of Chinese Medicine ranked first in both publication output and citation count.

Table 2 Top 10 institutions related to ferroptosis and pyroptosis in depression.

Type	Rank	Institution	Documents	Citations	Total link strength
Ferroptosis in depression	1	Guangzhou University of Chinese Medicine	7	69	22
	2	Nanchang University	6	87	8
	3	Harbin Medical University	6	61	0
	4	Jinan University	5	128	15
	5	Henan University of Chinese Medicine	5	37	10
	6	Soochow University	5	230	9
	7	Beijing University of Chinese Medicine	5	131	8
	8	Zhengzhou University	4	41	9
	9	Kunming Medical University	4	777	8
	10	Gannan Medical University	4	48	7
Pyroptosis in depression	1	Nanjing University of Chinese Medicine	26	2212	18
	2	Beijing University of Chinese Medicine	25	458	25
	3	Huazhong University of Science and Technology	23	932	19
	4	Fudan University	21	1308	15
	5	Nanjing Medical University	17	1109	19
	6	China Pharmaceutical University	17	1825	8
	7	Shanghai Jiao Tong University	16	693	23
	8	Capital Medical University	16	678	13
	9	Chongqing Medical University	16	903	5
	10	Shanghai University of Traditional Chinese Medicine	15	313	19

Figure 4 presents the collaboration networks among institutions in the 2 research areas. Figure 4A and B illustrate the collaboration networks among institutions in the fields of “ferroptosis in depression” and “pyroptosis in depression,” respectively. Guangzhou University of Chinese Medicine and Nanjing University of Chinese Medicine showed the highest centrality in the ferroptosis and pyroptosis networks, respectively. This suggests that they occupied relatively central positions within their respective institutional collaboration networks. However, institutional cooperation still exhibited clear geographical limitations. Therefore, to achieve greater breakthroughs in these 2 fields, it is strongly recommended that regional and disciplinary barriers be overcome and broader collaboration and academic exchange among research institutions be promoted.

Figure 4 Institutional collaboration networks in ferroptosis- and pyroptosis-related depression research. A: Institutional collaboration network in the field of ferroptosis in depression; B: Institutional collaboration network in the field of pyroptosis in depression. In both panels, each node represents an institution, and the node size is proportional to the number of publications. The lines between nodes represent collaborative relationships, with thicker lines indicating stronger collaboration. Different colors represent different institutional collaboration clusters.

Authors and co-cited authors analysis

A total of 1146 and 5330 authors contributed to publications on “ferroptosis in depression” and “pyroptosis in depression,” respectively. The top 10 most productive authors and the top 10 most co-cited authors in these 2 fields are listed in Table 3. In the field of “ferroptosis in depression,” Luo Qiang ranked first with 5 publications, followed by Ren Peng (n = 4), Zhao Yulong (n = 4), Zhou Junjie (n = 4), Zhao Xiujuan (n = 4), and Wang Jing (n = 4). In the field of “pyroptosis in depression,” Zhang Yi ranked first with 16 publications, followed by Jiang Chun-Lei (n = 11) and Jiang Pei (n = 10). Notably, all of the top 10 authors in both fields were from China, which is consistent with the distribution pattern observed for the leading institutions.

Table 3 Top 10 authors and co-cited authors related to ferroptosis and pyroptosis in depression.

Type	Rank	Author	Documents	Citations	Total link strength	Co-cited author	Citations
Ferroptosis in depression	1	Luo Qiang	5	53	29	Dixon SJ	73
	2	Ren Peng	4	48	28	Wang Y	58
	3	Zhao Yulong	4	48	28	Stockwell BR	43
	4	Zhou Junjie	4	48	28	Yang WS	37
	5	Zhao Xiujuan	4	51	20	Chen X	35
	6	Wang Jing	4	38	13	Jiao HY	34
	7	Li Xue	3	13	24	Dang RZ	34
	8	Wu Xiaoyun	3	13	24	Li J	33
	9	Yao Ranqi	3	51	20	Doll S	30
	10	Yu Ziran	3	51	20	Cao H	29
Pyroptosis in depression	1	Zhang Yi	16	976	22	Alcocer-Gomez E	385
	2	Jiang Chunlei	11	937	28	Zhang Y	338
	3	Jiang Pei	10	602	4	Maes M	239
	4	Wang Wei	9	368	10	Iwata M	203
	5	Hu Gang	9	1333	8	Pan Y	189
	6	Lu Ming	8	882	8	Miller AH	188
	7	Su Wenjun	7	524	20	Kaufmann FN	134
	8	Yu Jin	7	883	8	Willner P	123
	9	Xiao Ling	7	207	5	Li Y	107
	10	Yang Yang	7	138	3	Liu Y	103

Figure 5A and B illustrate the collaboration networks among authors in the fields of “ferroptosis in depression” and “pyroptosis in depression,” respectively. Different colors represent different collaboration clusters, and the lines between nodes indicate the strength of collaboration. These clusters reveal the major collaborative relationships and researchers in each field. In the “ferroptosis in depression” field, 4 major collaboration clusters were identified, among which the red cluster included Luo Qiang, Ren Peng, Zhou Junjie, and Wu Xiaoyun. In the “pyroptosis in depression” field, 6 collaboration clusters were formed, with the most influential cluster led by Zhang Yi and Jiang Chun-Lei, both of whom were also among the most productive authors. This indicates that a relatively stable collaborative network has been established among the major contributors in this field. However, most author collaborations were still largely confined within China, suggesting that international communication and collaboration among researchers from different countries should be further strengthened to generate higher-quality academic outputs in these fields.

Figure 5 Co-authorship and co-cited-author networks in ferroptosis- and pyroptosis-related depression research. A: Co-authorship network in ferroptosis-related depression research; B: Co-authorship network in pyroptosis-related depression research; C: Co-cited-author network in ferroptosis-related depression research; D: Co-cited-author network in pyroptosis-related depression research. In all panels, each node represents an author, and the node size is proportional to the number of publications in panels A and B or the number of co-citations in panels C and D. Links between nodes represent co-authorship relationships in panels A and B and co-citation relationships in panels C and D. Different colors indicate different collaboration or co-citation clusters.

In addition, 9147 and 33587 co-cited authors were identified in publications related to “ferroptosis in depression” and “pyroptosis in depression,” respectively. In the field of “ferroptosis in depression,” Dixon SJ ranked first with 73 co-citations, followed by Wang Y (n = 58) and Stockwell BR (n = 43) (Figure 5C). In the field of “pyroptosis in depression,” the top 3 most co-cited authors were Alcocer-Gómez E (385 co-citations), followed by Zhang Y (n = 338) and Maes M (n = 239) (Figure 5D). Meanwhile, Zhang Y ranked among the top 10 in both publication output and co-citation frequency, underscoring his important role and influence as a core leader in this field.

Journals and co-cited journals analysis

A total of 95 and 297 academic journals published articles in the fields of “ferroptosis in depression” and “pyroptosis in depression,” respectively. The top 10 journals with the highest publication output and the top 10 most co-cited journals in these 2 fields are listed in Table 4. International Journal of Molecular Sciences (n = 9, impact factor = 4.9) and International Immunopharmacology (n = 43, impact factor = 4.7) ranked first in publication output in the fields of “ferroptosis in depression” and “pyroptosis in depression,” respectively (Figure 6A and B).

Figure 6 Journal co-occurrence and co-citation networks in ferroptosis- and pyroptosis-related depression research. A: Journal co-occurrence network of publications on ferroptosis in depression; B: Journal co-occurrence network of publications on pyroptosis in depression; C: Journal co-citation network in ferroptosis-related depression research; D: Journal co-citation network in pyroptosis-related depression research. In panels A and B, each node represents a journal, and the node size is proportional to the number of publications. Links indicate co-occurrence relationships between journals. In panels C and D, each node represents a journal, and the node size is proportional to the number of citations received from the analyzed publications. Links indicate co-citation relationships between journals. Different colors represent distinct journal clusters, and the distance between nodes reflects the strength of their relatedness.

Table 4 Top 10 journals and co-cited journals related to ferroptosis and pyroptosis in depression.

Type	Rank	Journal	Frequency	Citations	IF (2025)	JCR	Co-cited journal	Citations	IF (2025)	JCR
Ferroptosis in depression	1	International Journal of Molecular Sciences	9	346	4.9	Q1	International Journal of Molecular Sciences	242	4.9	Q1
	2	Phytomedicine	6	67	8.3	Q1	Frontiers in Pharmacology	190	4.7	Q1
	3	Journal of Ethnopharmacology	5	184	5.4	Q1	Cell	187	42.5	Q1
	4	Free Radical Biology and Medicine	5	28	8.2	Q1	Journal of Neuroinflammation	167	10.1	Q1
	5	Frontiers in Neuroscience	4	48	3.2	Q2	Free Radical Biology and Medicine	165	8.2	Q1
	6	Molecular Neurobiology	4	61	4.3	Q2	Journal of Ethnopharmacology	160	5.4	Q1
	7	Antioxidants	4	254	6.6	Q1	Redox Biology	148	11.9	Q1
	8	Redox Biology	4	199	11.9	Q1	Biomedicine & Pharmacotherapy	139	7.5	Q1
	9	Frontiers in Immunology	4	395	5.9	Q1	Molecular Neurobiology	139	4.3	Q2
	10	Behavioural Brain Research	3	72	2.3	Q2	Oxidative Medicine and Cellular Longevity	136	6.1	Q1
Pyroptosis in depression	1	International Immunopharmacology	43	1152	4.7	Q1	Brain, Behavior, and Immunity	2174	7.6	Q1
	2	Brain, Behavior, and Immunity	27	2987	7.6	Q1	Journal of Neuroinflammation	1471	10.1	Q1
	3	International Journal of Molecular Sciences	27	1101	4.9	Q1	Molecular Psychiatry	1069	10.1	Q1
	4	Frontiers in Pharmacology	26	654	4.7	Q1	International Journal of Molecular Sciences	998	4.9	Q1
	5	Journal of Neuroinflammation	22	2999	10.1	Q1	Nature	932	49.5	Q1
	6	Behavioural Brain Research	17	745	2.3	Q2	Biological Psychiatry	879	9.0	Q1
	7	Molecular Neurobiology	17	546	4.3	Q2	Behavioural Brain Research	853	2.3	Q2
	8	Phytomedicine	14	190	8.3	Q1	Journal of Neuroscience	803	4.8	Q1
	9	Frontiers in Immunology	14	543	5.9	Q1	Proceedings of the National Academy of Sciences of the United States of America	785	13.1	Q1
	10	Scientific Reports	12	403	4.9	Q1	Frontiers in Pharmacology	706	4.7	Q1

IF: Impact factor; JCR: Journal Citation Reports.

Meanwhile, co-citation analysis showed that the most frequently co-cited journals in the fields of “ferroptosis in depression” and “pyroptosis in depression” were International Journal of Molecular Sciences (n = 242) and Brain, Behavior, and Immunity (n = 2174), respectively (Figure 6C and D). This suggests that these journals occupy prominent positions within the citation networks of the corresponding research areas. However, citation frequency should be interpreted cautiously because it may be influenced by publication time, database coverage, and disciplinary citation practices. Among the top 10 journals ranked by publication output and co-citation frequency, most were classified as Journal Citation Reports (JCR) Q1, with Nature having the highest impact factor of 49.5. However, journal impact factor and co-citation frequency should be interpreted as bibliometric characteristics rather than direct measures of article quality or clinical relevance.

The dual-map overlay of journals (Figure 7) was generated using CiteSpace, illustrating the disciplinary distribution of journals and their citation relationships. In this map, the left side represents clusters of citing journals, the right side represents clusters of cited journals, and the colored paths indicate citation trajectories between disciplines. The analysis identified a prominent orange citation path, indicating that studies on “ferroptosis in depression” and “pyroptosis in depression” were mainly published in journals related to molecular biology, immunology, and clinical medicine, such as International Journal of Molecular Sciences, Brain, Behavior, and Immunity, Journal of Neuroinflammation, and Frontiers in Pharmacology. These studies were primarily supported by and cited literature published in high-impact journals in psychiatry, neuroscience, and multidisciplinary science, such as Molecular Psychiatry, Biological Psychiatry, Journal of Neuroscience, and PNAS. This finding suggests that research in this field has a marked interdisciplinary nature, requiring collaborative efforts across molecular mechanisms, neuroimmunology, and psychiatry.

Figure 7 Dual-map overlay of journals in ferroptosis- and pyroptosis-related depression research. A: Dual-map overlay of journals in ferroptosis-related depression research; B: Dual-map overlay of journals in pyroptosis-related depression research. In each panel, the clusters on the left represent citing journals, whereas those on the right represent cited journals. The colored citation paths indicate citation relationships between disciplines, and the width of each path is proportional to citation frequency.

Co-cited references analysis

Co-cited references refer to 2 or more publications that are cited together by a subsequent article, thereby forming a co-citation relationship. Table 5 presents detailed information on the top 10 most co-cited references in the 2 fields. As shown in Figure 8A, the article entitled “Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death,” published in Cell by Dixon et al[8], was the most frequently co-cited reference in the field of “ferroptosis in depression.” This study introduced ferroptosis as an iron-dependent form of regulated cell death that is distinct from apoptosis, necrosis, and autophagy. It subsequently became a frequently co-cited foundational reference in the ferroptosis dataset. It was followed by the article by Jiao et al[23], published in Neuropsychiatric Disease and Treatment, entitled “Traditional Chinese Formula Xiaoyaosan Alleviates Depressive-Like Behavior in CUMS Mice by Regulating PEBP1-GPX4-Mediated Ferroptosis in the Hippocampus.” This study emphasized the close association between abnormal hippocampal ferroptosis and depressive-like behaviors and further revealed that the traditional Chinese medicine formula Xiaoyaosan may exert antidepressant effects by inhibiting ferroptosis through modulation of the phosphatidylethanolamine-binding protein 1/GPX4 signaling axis, thereby providing experimental evidence for the involvement of ferroptosis in the pathological mechanisms of depression and for the therapeutic potential of traditional Chinese medicine interventions[24,25].

Figure 8 Co-cited-reference networks and references with the strongest citation bursts in ferroptosis- and pyroptosis-related depression research. A: Co-cited-reference network in ferroptosis-related depression research; B: Co-cited-reference network in pyroptosis-related depression research; C: Top 20 references with the strongest citation bursts in ferroptosis-related depression research; D: Top 20 references with the strongest citation bursts in pyroptosis-related depression research. In panels A and B, each node represents a cited reference, and the node size is proportional to its co-citation frequency. Links between nodes indicate co-citation relationships, and different colors represent distinct co-citation clusters. In panels C and D, the red segments indicate periods during which references experienced citation bursts; the strength and duration of each burst are shown.

Table 5 Top 10 co-cited references associated with ferroptosis and pyroptosis in depression.

Type	Rank	Reference	Citations	Title	DOI	Source
Ferroptosis in depression	1	Dixon SJ (2012)	61	Ferroptosis: An iron-dependent form of nonapoptotic cell death	10.1016/j.cell.2012.03.042	Cell
	2	Jiao H (2021)	34	Traditional Chinese formula Xiaoyaosan alleviates depressive-like behavior in CUMS mice by regulating PEBP1-GPX4-mediated ferroptosis in the hippocampus	10.2147/NDT.S302443	Neuropsychiatric Disease and Treatment
	3	Dang R (2022)	34	Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway	10.1186/s12974-022-02400-6	Journal of Neuroinflammation
	4	Stockwell BR (2017)	26	Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease	10.1016/j.cell.2017.09.021	Cell
	5	Cao H (2021)	25	Hippocampal proteomic analysis reveals activation of necroptosis and ferroptosis in a mouse model of chronic unpredictable mild stress-induced depression	10.1016/j.bbr.2021.113261	Behavioural Brain Research
	6	Jiang X (2021)	23	Ferroptosis: Mechanisms, biology and role in disease	10.1038/s41580-020-00324-8	Nature Reviews Molecular Cell Biology
	7	Wang X (2023)	22	Saikosaponin B2 ameliorates depression-induced microglia activation by inhibiting ferroptosis-mediated neuroinflammation and ER stress	10.1016/j.jep.2023.116729	Journal of Ethnopharmacology
	8	Wang Y (2021)	17	Hydrogen sulfide alleviates the anxiety-like and depressive-like behaviors of type 1 diabetic mice via inhibiting inflammation and ferroptosis	10.1016/j.lfs.2021.119551	Life Sciences
	9	Wang L (2023)	17	Targeting the ferroptosis crosstalk: Novel alternative strategies for the treatment of major depressive disorder	10.1136/gpsych-2023-101072	General Psychiatry
	10	Doll S (2019)	16	FSP1 is a glutathione-independent ferroptosis suppressor	10.1038/s41586-019-1707-0	Nature
Pyroptosis in depression	1	Alcocer-Gómez E (2014)	189	NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder	10.1016/j.bbi.2013.10.017	Brain, Behavior, and Immunity
	2	Pan Y (2014)	166	Microglial NLRP3 inflammasome activation mediates IL-1β-related inflammation in prefrontal cortex of depressive rats	10.1016/j.bbi.2014.04.007	Brain, Behavior, and Immunity
	3	Kaufmann FN (2017)	130	NLRP3 inflammasome-driven pathways in depression: Clinical and preclinical findings	10.1016/j.bbi.2017.03.002	Brain, Behavior, and Immunity
	4	Miller AH (2016)	102	The role of inflammation in depression: From evolutionary imperative to modern treatment target	10.1038/nri.2015.5	Nature Reviews Immunology
	5	Iwata M (2013)	99	The inflammasome: Pathways linking psychological stress, depression, and systemic illnesses	10.1016/j.bbi.2012.12.008	Brain, Behavior, and Immunity
	6	Zhang Y (2015)	98	NLRP3 inflammasome mediates chronic mild stress-induced depression in mice via neuroinflammation	10.1093/ijnp/pyv006	International Journal of Neuropsychopharmacology
	7	Zhang Y (2014)	95	Involvement of inflammasome activation in lipopolysaccharide‐induced mice depressive‐like behaviors	10.1111/cns.12170	CNS Neuroscience & Therapeutics
	8	Iwata M (2016)	92	Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor	10.1016/j.biopsych.2015.11.026	Biological Psychiatry
	9	Xu Y (2016)	82	NLRP3 inflammasome activation mediates estrogen deficiency-induced depression-and anxiety-like behavior and hippocampal inflammation in mice	10.1016/j.bbi.2016.02.022	Brain, Behavior, and Immunity
	10	Yue N (2017)	79	Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors	10.1186/s12974-017-0865-y	Journal of Neuroinflammation

CUMS: Chronic unpredictable mild stress; DOI: Digital object identifier; ER: Endoplasmic reticulum; FSP1: Ferroptosis suppressor protein 1; GPX4: Glutathione peroxidase 4; HO-1: Heme oxygenase-1; NLRP3: NOD-like receptor family pyrin domain-containing 3; Nrf2: Nuclear factor erythroid 2-related factor 2; PEBP1: Phosphatidylethanolamine-binding protein 1; P2X7: P2X purinoceptor 7; Sirt1: Sirtuin 1.

As shown in Figure 8B, the article by Alcocer-Gómez et al[26], published in Brain, Behavior, and Immunity, entitled “NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder,” was the most frequently co-cited reference in the analyzed dataset related to “pyroptosis in depression.” This study reported NLRP3 inflammasome activation in peripheral blood mononuclear cells from patients with major depressive disorder. It also described associations between depressive status and caspase-1-dependent inflammatory signaling, including IL-1β and IL-18 release. It therefore provided important evidence for the involvement of pyroptosis and inflammasome activation in the pathological mechanisms of depression. These frequently co-cited articles were mainly published in well-established journals such as Brain, Behavior, and Immunity and Nature Reviews Immunology, with Brain, Behavior, and Immunity alone contributing 5 of the top 10 most highly cited articles in the field of “pyroptosis in depression.” Collectively, these references covered a broad range of topics related to ferroptosis and pyroptosis in depression, including regulation, molecular mechanisms, targeted inhibition, and therapeutic intervention.

Emerging references are those that experience a sharp increase in citation frequency over a short period, thereby reflecting research hotspots and frontier trends during a specific time frame. Figure 8C and D present the top 20 references with the strongest citation bursts in the fields of ferroptosis in depression and pyroptosis in depression, respectively. In the field of “ferroptosis in depression,” the article by Stockwell et al[25], published in Cell, entitled “Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease,” showed the strongest citation burst (8.75) during 2019–2022. In addition, 10 references continued to show citation bursts through 2026. These references mainly focused on the morphological characteristics, molecular regulatory mechanisms, signaling pathways, inducers, and inhibitors of ferroptosis, as well as its potential roles in neurological diseases and depression, indicating that the mechanisms of ferroptosis and their translational implications in disease remain major frontier topics of sustained interest.

In the field of “pyroptosis in depression,” the article by Alcocer-Gómez et al[26], published in Brain, Behavior, and Immunity, entitled “NLRP3 Inflammasome Is Activated in Mononuclear Blood Cells from Patients with Major Depressive Disorder,” exhibited the strongest citation burst (24.4) during 2019. Additionally, 4 references maintained citation bursts through 2026. These studies mainly focused on NLRP3 inflammasome activation, caspase-1-dependent inflammatory responses, the release of IL-1β and IL-18, and the relationship between neuroinflammation and the onset and progression of depression. Together, they further clarified the close association between pyroptosis-related inflammatory mechanisms and the pathological process of depression and provided new perspectives for targeting the inflammasome and pyroptosis pathways as potential intervention strategies for depression.

Keyword analysis

Keywords provide a highly condensed summary of article content, and keyword co-occurrence analysis can help reveal research hotspots and development trends within a given field. Table 6 presents the most frequently occurring keywords and their TLS in the fields of “ferroptosis in depression” and “pyroptosis in depression.”

Table 6 Top 10 most frequently occurring keywords associated with ferroptosis and pyroptosis in depression.

Type	Rank	Keyword	Occurrences	Total link strength
Ferroptosis in depression	1	Ferroptosis	121	414
	2	Depression	73	287
	3	Oxidative stress	31	145
	4	Activation	28	125
	5	Neuroinflammation	25	112
	6	Inflammation	21	95
	7	Expression	19	79
	8	Iron	18	98
	9	Cell death	16	76
	10	Cognitive impairment	13	67
Pyroptosis in depression	1	Depression	488	3756
	2	NLRP3 inflammasome	342	2583
	3	Neuroinflammation	252	1971
	4	Activation	214	1734
	5	Inflammation	158	1211
	6	Stress	137	1113
	7	Inflammasome	128	975
	8	Microglia	125	1056
	9	Oxidative stress	124	922
	10	Brain	120	984

NLRP3: NOD-like receptor family pyrin domain-containing 3.

As shown in Figure 9A, in the field of “ferroptosis in depression,” excluding the search terms themselves, the top 5 high-frequency keywords were “depression,” “oxidative stress,” “activation,” “neuroinflammation,” and “inflammation.” These results indicate that research in this field mainly focuses on diseases such as depression, cognitive impairment, Alzheimer’s disease, Parkinson’s disease, and anxiety; pathological mechanisms including oxidative stress, neuroinflammation, inflammation, iron overload/iron metabolism disorder, and cell death; drug-related studies represented by antidepressants, quercetin, traditional Chinese medicine, natural products, and ferrostatin-1; and signaling pathways centered on GPX4, nuclear factor erythroid 2-related factor 2/heme oxygenase-1, iron metabolism, lipid peroxidation, and autophagy.

Figure 9 Keyword co-occurrence networks and keyword-cluster analyses in ferroptosis- and pyroptosis-related depression research. A: Keyword co-occurrence network of ferroptosis-related depression research; B: Keyword co-occurrence network of pyroptosis-related depression research; C: Keyword-cluster analysis of ferroptosis-related depression research; D: Keyword-cluster analysis of pyroptosis-related depression research. In panels A and B, each node represents a keyword, the node size is proportional to keyword frequency, links indicate co-occurrence relationships, and different colors represent distinct keyword clusters. In panels C and D, the labeled clusters represent major thematic groups identified using CiteSpace; different colors and shaded areas indicate distinct clusters.

As shown in Figure 9B, in the field of “pyroptosis in depression,” the high-frequency keywords mainly included “depression,” “NLRP3 inflammasome,” “neuroinflammation,” “activation,” “inflammation,” and “stress.” These findings suggest that research in this field primarily focuses on diseases or related phenotypes such as major depressive disorder, anxiety-like behavior, brain injury, cognitive impairment, and mouse models; pathological mechanisms including NLRP3 inflammasome activation, neuroinflammation, microglial activation, oxidative stress, and inflammatory responses; and signaling pathways involving nuclear factor-κB, caspase-1, IL-1β, IL-18, and inflammasome signaling.

Based on keyword co-occurrence analysis, further clustering of keywords with similar features can reflect the fundamental knowledge structure of a research field. In CiteSpace, the modularity Q value and silhouette S value are used to evaluate the significance of the clustering structure and the reliability of the clustering results, respectively. In general, Q > 0.3 indicates a significant clustering structure, S > 0.5 indicates reasonable clustering, and S > 0.7 suggests that the clustering results are highly credible.

Figure 9C shows the clustering results of keywords in the field of “ferroptosis in depression” generated by CiteSpace. The network had a Q value of 0.4627 and an S value of 0.809, indicating a significant clustering structure and reliable results. According to the automatically generated labels shown in the figure, this field formed several relatively distinct thematic clusters. These labels were interpreted in the Discussion in relation to the biological questions and research directions represented by the corresponding keyword groups, including #0 cox4i1, #1 gut microbiota, #3 autophagy, #4 natural products, #5 ferulic acid, #7 antipsychotics, #10 comorbidity of pain and depression, #12 autosomal degradation, and #15 Bushen Hanyu Huayu formula. Overall, the ferroptosis clusters covered 3 themes: Molecular mechanisms, disease associations, and potential interventions. The mechanistic clusters involved oxidative stress, autophagy, mitochondrial dysfunction, and iron dysregulation. Other clusters addressed gut microbiota, comorbid pain and depression, neurodegenerative diseases, natural products, traditional Chinese medicine formulas, and ferroptosis-targeted strategies. These patterns suggest increasing interest in translational applications.

As shown in Figure 9D, keywords related to “pyroptosis in depression” were also clustered into multiple thematic groups, with a Q value of 0.386 and an S value of 0.7237, indicating that the research topics were relatively clear and the clustering results were reliable. According to the labels in the figure, the main clusters in this field included #0 major depressive disorder, #1 mitochondrial dysfunction, #2 Alzheimer’s disease, #3 chronic unpredictable mild stress, #4 ginsenoside Rg3, #6 neuronal pyroptosis, #8 suicide risk, #10 central nervous system, #11 histone acetylation, and #13 IL-1β. Overall, these clusters mainly focused on several major aspects. First, they addressed the regulatory mechanisms of pyroptosis and the NLRP3 inflammasome in depression, involving neuroinflammation, mitochondrial dysfunction, IL-1β release, and neuronal pyroptosis. Second, they explored the associations between depression and Alzheimer’s disease, suicide risk, and central nervous system disorders. In addition, they included mechanistic studies using chronic unpredictable mild stress models and potential therapeutic strategies, exemplified by ginsenoside Rg3, reflecting a trend in this field from basic inflammatory mechanisms toward clinical relevance and intervention-oriented research.

DISCUSSION

General information

The present study systematically analyzed the literature in the fields of “ferroptosis in depression” and “pyroptosis in depression” using bibliometric methods. Overall, both research areas have shown continuous growth, although their developmental trajectories differed. Research on “pyroptosis in depression” emerged earlier and expanded steadily over time, whereas research on “ferroptosis in depression” started relatively late but has grown rapidly in recent years, suggesting that it has become an emerging hotspot and may remain an important frontier in the near future.

From the perspective of countries and institutions, China and the United States were the 2 leading contributors in both fields, ranking at the top in terms of publication output and citation impact. This finding highlights the prominent roles of these 2 countries in advancing research on depression-related regulated cell death. In particular, most of the leading institutions were from China, indicating that these topics have attracted substantial attention there. Guangzhou University of Chinese Medicine and Nanjing University of Chinese Medicine showed strong performance in the fields of “ferroptosis in depression” and “pyroptosis in depression,” respectively, suggesting that they play important roles in promoting relevant studies. However, despite the high productivity of several institutions, cooperation patterns still showed obvious regional aggregation, and international collaboration remained less intensive than domestic collaboration. Therefore, establishing broader, more stable international research networks may be essential for achieving deeper mechanistic insights and higher-quality outputs in these 2 fields. In terms of authorship, the most productive authors in both fields were predominantly Chinese, consistent with the institutional distribution. Author collaboration networks suggested that several relatively stable research groups have already formed, especially in the pyroptosis field. Nevertheless, collaboration among authors was still concentrated within domestic teams, and cross-national cooperation remained insufficient. Because the mechanisms of depression involve complex interactions among neurobiology, immunology, oxidative stress, and metabolism, stronger interdisciplinary and international cooperation is likely to accelerate progress in both fields.

Regarding journals, the core publication outlets in these 2 fields included International Journal of Molecular Sciences, International Immunopharmacology, Brain, Behavior, and Immunity, and Journal of Neuroinflammation. Most of the high-yield and highly cited journals belonged to JCR Q1, indicating that this topic has already attracted considerable attention from high-quality journals. In addition, dual-map overlay analysis showed that studies on ferroptosis and pyroptosis in depression were mainly published in journals related to molecular biology, immunology, and clinical medicine, while the cited knowledge base was concentrated in psychiatry, neuroscience, and multidisciplinary high-impact journals. This pattern reflects the strongly interdisciplinary nature of this topic and suggests that progress in this field relies on the integration of molecular mechanism research, neuroimmune studies, and psychiatric investigation.

Co-citation analysis further identified the foundational literature in both fields. In the “ferroptosis in depression” field, the article by Dixon et al[8], published in Cell, which first defined ferroptosis as an iron-dependent non-apoptotic form of cell death, was the most frequently co-cited reference, highlighting its central theoretical role. In the “pyroptosis in depression” field, the article by Alcocer-Gómez et al[26], published in Brain, Behavior, and Immunity, which demonstrated abnormal activation of the NLRP3 inflammasome in patients with major depressive disorder, was the most influential co-cited reference. Together, these frequently co-cited studies contributed important theoretical and clinical evidence that informed subsequent work on the involvement of ferroptosis and pyroptosis in depression.

Ferroptosis in depression

Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation and oxidative stress, and it has increasingly been implicated in a variety of neuropsychiatric and neurodegenerative disorders. In the present study, the most frequent keywords in the field of ferroptosis in depression, aside from the search terms themselves, included depression, oxidative stress, activation, neuroinflammation, and inflammation. These findings suggest that current research in this field is primarily focused on the intersection of ferroptosis with redox imbalance, inflammatory activation, and depression-related neuropathology.

Oxidative stress appears to be a central mechanism linking ferroptosis to depression[27]. Excessive production of ROS can promote lipid peroxidation, damage cellular membranes, and disrupt neuronal homeostasis, thereby facilitating ferroptotic injury[28]. At the same time, disordered iron metabolism may further amplify oxidative injury through Fenton chemistry, creating a vicious cycle of ROS accumulation and lipid peroxidation[29,30]. Because brain regions closely related to emotional regulation, such as the hippocampus and prefrontal cortex, are especially vulnerable to oxidative damage, ferroptosis may represent an important mechanistic bridge connecting metabolic disturbance with depressive phenotypes[31].

Neuroinflammation is another major focus of current research. Ferroptosis may aggravate inflammatory responses by releasing danger-associated molecules and lipid peroxidation byproducts, which in turn activate microglia and other immune pathways[32,33]. Conversely, inflammatory cytokines may disrupt iron homeostasis and antioxidant defense systems, thereby promoting ferroptotic vulnerability[34,35]. This reciprocal interaction may explain why neuroinflammation, inflammation, and activation emerged as central keywords in this field. In addition, the keyword clusters related to autophagy, gut microbiota, natural products, and comorbidity of pain and depression indicate that current research is extending beyond traditional cell death mechanisms and increasingly exploring broader biological systems and translational applications.

Notably, therapeutic exploration has become an important emerging direction. The appearance of clusters such as natural products, ferulic acid, and Bushen Hanyu Huayu formula, together with high-frequency keywords such as quercetin, traditional Chinese medicine, and ferrostatin-1, suggests growing attention to ferroptosis-targeted interventions. These studies imply that modulation of the GPX4, nuclear factor erythroid 2-related factor 2/heme oxygenase-1, iron metabolism, and lipid peroxidation pathways may provide novel antidepressant strategies[36-38]. Therefore, the field of ferroptosis in depression appears to be transitioning from basic mechanistic exploration to translational research focused on therapeutic intervention and biomarker discovery.

Pyroptosis in depression

Pyroptosis is an inflammatory form of PCD driven mainly by inflammasome activation, especially the NLRP3 inflammasome, followed by caspase-1 activation, gasdermin-mediated membrane pore formation, and the release of inflammatory cytokines such as IL-1β and IL-18[39,40]. In the present study, the high-frequency keywords in the field of pyroptosis in depression included depression, NLRP3 inflammasome, neuroinflammation, activation, inflammation, and stress, highlighting that this field is primarily centered on the neuroimmune and inflammatory mechanisms of depression.

This pattern is highly consistent with the current view that depression is closely associated with chronic low-grade inflammation and immune dysregulation[41,42]. Activation of the NLRP3 inflammasome in microglia and peripheral immune cells may trigger a cascade of inflammatory events that affect synaptic plasticity, neurotransmitter systems, neuroendocrine regulation, and neuronal survival, thereby contributing to depressive symptoms[43,44]. The clustering results further support this interpretation, as major clusters included major depressive disorder, mitochondrial dysfunction, chronic unpredictable mild stress, neuronal pyroptosis, and IL-1β. These findings indicate that the field has evolved from general descriptions of inflammation toward more precise investigations of inflammasome-mediated neuronal injury and stress-induced depressive pathology.

The link between mitochondrial dysfunction and pyroptosis therefore deserves particular attention. Mitochondrial damage can increase ROS production and release mitochondrial danger signals, thereby facilitating NLRP3 inflammasome activation[45,46]. This suggests that mitochondrial dysfunction may function as an upstream event connecting cellular stress to neuroinflammatory damage in depression[47]. Similarly, microglial activation emerged as an important keyword, consistent with evidence that overactivated microglia can mediate inflammatory amplification and contribute to synaptic and neuronal abnormalities in depression[48,49].

In addition, the presence of clusters such as ginsenoside Rg3 indicates that the field is also moving toward therapeutic application. Current studies suggest that targeting the NLRP3/caspase-1/IL-1β axis, suppressing microglial overactivation, and reducing mitochondrial stress may represent promising strategies for antidepressant intervention[43]. Therefore, research on pyroptosis in depression is gradually expanding from mechanistic studies to the identification of anti-inflammatory therapeutic targets and potential clinically relevant interventions.

Association between ferroptosis and pyroptosis

Our integrated analysis identified only 17 publications that simultaneously addressed ferroptosis and pyroptosis in depression, representing 11% of the ferroptosis dataset and 2% of the pyroptosis dataset. This limited overlap indicates that the 2 fields are still investigated predominantly as separate research streams. Although ferroptosis and pyroptosis share several pathological contexts in depression, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and microglial activation, they remain biologically distinct forms of regulated cell death. Ferroptosis is characterized primarily by iron-dependent lipid peroxidation and failure of antioxidant defense systems[50,51], whereas pyroptosis is generally associated with inflammasome activation, caspase activation, gasdermin-mediated membrane pore formation, and inflammatory cytokine release[52]. Therefore, the overlap of high-frequency keywords between the 2 bibliometric datasets should be interpreted as evidence of shared research contexts rather than direct proof of mechanistic integration. Importantly, the current literature appears to remain largely separated into 2 research streams. Studies of ferroptosis in depression mainly examine iron metabolism, lipid peroxidation, GPX4-related antioxidant defense, and ferroptosis-targeted interventions. By contrast, studies categorized as pyroptosis-related mainly focus on NLRP3 inflammasome activation, caspase-1-dependent inflammatory signaling, IL-1β/IL-18 release, and microglia-mediated neuroinflammation. Relatively few studies have simultaneously evaluated canonical markers of both ferroptosis and pyroptosis in the same depression model, determined whether one pathway precedes or drives the other, or tested whether dual-pathway intervention provides benefits beyond targeting either pathway alone.

Oxidative stress, mitochondrial dysfunction, and neuroinflammation may represent potential points of convergence between the 2 pathways. For example, lipid peroxidation and ROS generated during ferroptotic stress may facilitate inflammasome activation, whereas inflammatory mediators associated with pyroptosis may worsen redox imbalance and disrupt iron homeostasis[53]. However, these proposed links remain largely inferential in the context of depression. Shared pathways do not necessarily indicate direct crosstalk, and whether ferroptosis and pyroptosis occur sequentially, in parallel, or independently across different cell types and disease stages remains unclear.

Future integrated mechanistic studies should assess ferroptosis- and pyroptosis-related markers simultaneously in well-characterized depression models and clinical samples. Particular attention should be paid to cell-type specificity in neurons, microglia, astrocytes, and peripheral immune cells; temporal relationships between lipid peroxidation and inflammasome activation; and potential regulatory nodes linking the 2 processes, such as ROS, mitochondrial damage, iron metabolism, and gasdermin-related signaling. Experimental studies using genetic or pharmacological inhibition of one pathway followed by assessment of the other, as well as combined-target intervention studies, will be important for determining whether the 2 forms of cell death have a true causal interaction and whether their co-targeting has translational value in depression.

Another central point of convergence is neuroinflammation. Pyroptosis directly induces inflammatory cascades through inflammasome activation and cytokine release, whereas ferroptosis may secondarily stimulate immune activation by producing lipid peroxidation-derived danger signals. In the context of depression, where neuroinflammation is already recognized as a major pathogenic mechanism, the interaction between ferroptosis and pyroptosis may create a self-perpetuating cycle that intensifies neuronal dysfunction and behavioral abnormalities.

Implications and future directions

The present bibliometric findings provide several important implications for future research. First, they confirm that ferroptosis and pyroptosis have become increasingly important conceptual frameworks for understanding the biological basis of depression. Second, the identified hotspots suggest that future studies will likely continue to focus on oxidative stress, iron metabolism, NLRP3 inflammasome signaling, microglial activation, and targeted intervention strategies. Third, the frequent appearance of keywords related to natural products, traditional Chinese medicine, and signaling pathway regulation indicates increasing interest in translational and therapeutic applications. However, these bibliometric trends should be interpreted as indicators of research attention rather than direct evidence of therapeutic effectiveness or clinical readiness.

It should also be noted that bibliometric influence does not necessarily equate to scientific novelty or clinical utility. Traditional citation indicators are cumulative and time-dependent; thus, foundational studies and earlier publications are more likely to achieve high citation counts, whereas recent studies may not yet have received sufficient citations despite potentially important methodological or translational contributions. In addition, citation behavior may be affected by journal visibility, research field size, and database coverage. Future bibliometric investigations may combine conventional citation and co-citation analyses with citations per year, field-normalized citation indicators, altmetric attention scores, and evidence of clinical translation, such as inclusion in clinical guidelines or policy documents. This approach may enable a more comprehensive evaluation of the impact of emerging research on ferroptosis and pyroptosis in depression.

However, several challenges remain. Much of the current literature is still dominated by basic and preclinical research, while direct clinical evidence remains relatively limited. More large-scale clinical studies are needed to determine whether ferroptosis- and pyroptosis-related molecules can serve as reliable diagnostic biomarkers, prognostic indicators, or treatment response markers in patients with depression. In addition, future studies should further strengthen multicenter collaboration, improve methodological consistency, and integrate perspectives from psychiatry, neuroscience, immunology, and molecular biology to better clarify the roles of these regulated cell death pathways in depression.

The observed trends also have practical implications for research funding and experimental design. Funding agencies may prioritize multidisciplinary projects that link oxidative stress, iron metabolism, mitochondrial dysfunction, neuroinflammation, and inflammasome signaling rather than supporting isolated pathway-based investigations alone. In preclinical studies, ferroptosis should be evaluated using complementary evidence, including indices of iron homeostasis, lipid peroxidation, antioxidant defense, and appropriate ferroptosis-rescue experiments. Likewise, pyroptosis-related studies should distinguish inflammasome activation from bona fide pyroptotic cell death by assessing pathway-specific evidence, such as caspase activation, gasdermin cleavage or pore formation, membrane disruption, and inflammatory cytokine release. Standardized reporting of animal models, brain regions, cell types, intervention timing, and pathway-specific markers would improve reproducibility and facilitate comparisons across studies.

A major priority for future research is to move beyond parallel descriptions of ferroptosis and pyroptosis. Current evidence does not establish whether these pathways are directly coupled in depression or simply coexist as responses to common pathological stressors. Future studies should therefore assess canonical markers of both pathways simultaneously in well-characterized depression models and clinical samples. Longitudinal experimental designs, cell-type-resolved approaches, and genetic or pharmacological perturbation studies will be particularly important for distinguishing correlation from causal crosstalk. Attention should be paid to neurons, microglia, astrocytes, and peripheral immune cells, as well as to potential shared regulatory nodes, including ROS, mitochondrial damage, iron dysregulation, and inflammatory signaling.

From a translational perspective, a stepwise development strategy is warranted. First, candidate biomarkers related to iron metabolism, lipid peroxidation, antioxidant capacity, inflammasome activation, gasdermin signaling, IL-1β, and IL-18 should be evaluated in adequately powered clinical cohorts. Second, promising markers should be replicated in independent multicenter cohorts and assessed for their ability to identify biologically distinct patient subgroups, predict treatment response, or estimate relapse risk. Third, early-phase clinical trials of interventions targeting oxidative stress, iron metabolism, neuroinflammation, or inflammasome-related signaling should incorporate pharmacodynamic biomarkers and target-engagement outcomes before proceeding to large-scale efficacy trials. This biomarker-guided approach may help reduce the impact of biological heterogeneity in depression and clarify whether ferroptosis- and pyroptosis-related pathways can provide clinically meaningful targets for precision treatment.

Limitations

This study provides a comprehensive bibliometric overview of the research landscape of ferroptosis in depression and pyroptosis in depression, including publication trends, leading contributors, core journals, influential references, and emerging hotspots. It offers a valuable reference for researchers seeking to quickly understand the knowledge structure and future directions of these 2 rapidly developing fields. Nevertheless, several limitations should be acknowledged. First, the literature was retrieved solely from the WoSCC. Although WoSCC is widely used in bibliometric studies because of its standardized citation records and compatibility with visualization software, reliance on a single database may have introduced database coverage, language, and indexing biases. In particular, WoSCC predominantly indexes English-language journals and may underrepresent non-English publications, regional journals, local databases, and recently indexed records that could contain relevant research on ferroptosis, pyroptosis, and depression. Consequently, the present findings may not fully capture the entire global research landscape, especially research outputs from non-English-speaking regions. Future studies should integrate multiple databases, such as Scopus, PubMed, EMBASE, and relevant regional databases, and consider multilingual search strategies to improve the comprehensiveness and representativeness of bibliometric analyses. Second, the 2 datasets were analyzed separately; therefore, overlap in keywords, co-cited references, or broader pathological themes cannot by itself demonstrate direct biological crosstalk between ferroptosis and pyroptosis. The present bibliometric analysis can identify shared research contexts and potential points of convergence, but it cannot establish causal or temporal relationships between the 2 pathways. These relationships require validation through dedicated mechanistic and clinical studies. Third, recently published high-quality studies may be underestimated because of their shorter citation window. Although citation frequency and co-citation relationships remain widely used indicators for identifying the intellectual structure of a research field, future studies could complement conventional citation-based analyses with time-normalized indicators, such as citations per year and field-normalized citation impact, as well as alternative metrics (e.g., article views, downloads, social media attention, policy citations, and clinical guideline citations). Such multidimensional evaluation may provide a more balanced assessment of academic influence, societal attention, and potential clinical relevance. Finally, because both fields are still expanding rapidly, the identified hotspots and trends may evolve as new literature continues to emerge.

CONCLUSION

In summary, the present bibliometric analysis demonstrates that research on “ferroptosis in depression” and “pyroptosis in depression” is developing rapidly and shows marked interdisciplinary characteristics. Ferroptosis-related studies mainly focus on oxidative stress, iron metabolism, lipid peroxidation, antioxidant defense, and targeted inhibition, whereas pyroptosis-related studies primarily emphasize inflammasome activation, gasdermin-mediated inflammatory cell death, neuroinflammation, and cytokine-mediated injury. Although both fields share several pathological contexts, including oxidative stress and neuroinflammation, the current literature remains largely organized into separate research streams. Direct evidence demonstrating causal crosstalk, temporal sequencing, cell-type-specific interactions, and the therapeutic benefit of co-targeting ferroptosis and pyroptosis in depression remains limited. Future studies should therefore employ integrated mechanistic and clinical approaches to determine whether these pathways are truly interconnected and whether their combined modulation can yield clinically meaningful biomarkers or therapeutic strategies.

ACKNOWLEDGMENTS

The authors would like to express their sincere gratitude to all those who provided expert assistance in designing the search strategy and retrieving the core datasets from scientific databases. We also thank our colleagues for their meticulous work in study screening, data organization, and cross-checking of literature records and our advisors for their valuable insights regarding the analytical framework and the interpretation of collaborative networks. All individuals mentioned above have reviewed the original bibliometric data and the conclusions drawn from them and have agreed to be included in the acknowledgments.