Necroptosis is a lytic form of regulated cell death (RCD) that is dependent on receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain like pseudokinase (MLKL). This form of RCD has been implicated in various inflammatory diseases and organ injuries including cisplatin-induced acute kidney injury (AKI), thus representing a therapeutic target for such diseases. Theaflavin is an ingredient of black tea that exhibits beneficial effects on human health and has been shown to regulate pyroptosis, but its effects on necroptosis and cisplatin-induced AKI remain unclear. In this study, we found that theaflavin suppressed necroptosis in murine macrophages, MPC-5 podocytes and human HT-29 cells treated with TNF-α, Smac mimetic and IDN-6556 or LPS plus IDN-6556. The RIPK1/RIPK3/MLKL signaling axis in these cells treated with necroptosis inducers was effectively inhibited by theaflavin. The inhibition of necroptotic signaling was associated with attenuated mitochondrial dysfunction (as evidenced by decreased mitochondrial membrane potential and increased mitochondrial ROS production), reduced ubiquitination of RIPK1 and RIPK3, and blockade of necrosome. Furthermore, oral administration of theaflavin mitigated renal and hepatic injury in a mouse model of cisplatin-induced AKI. In agreement with in vitro cellular data, theaflavin decreased the levels of phosphorylated MLKL, an in vivo biomarker for necroptosis, in macrophages and other cells in the kidney and the liver of mice with cisplatin-induced AKI. Collectively, these results indicate that theaflavin can suppress necroptosis by attenuating RIPK1/RIPK3/MLKL signaling and thereby conferring protection against cisplatin-induced AKI, uncovering a previously unappreciated action of black tea components against necroptosis-related disorders.

PANoptosis represents a highly coordinated inflammatory programmed cell death governed by the assembly and activation of PANoptosome, which strategically integrate core molecular elements from pyroptosis, apoptosis, and necroptosis. The triple-component cell death pathways set themselves apart from alternative regulated cell death mechanisms through their unique capacity to concurrently integrate and process molecular signals derived from multiple death-signaling modalities, thereby coordinating a multifaceted cellular defense system against diverse pathological insults. Pathogen-associated molecular patterns synergistically interact with cytokine storms, and oncogenic stress to active PANoptosis, establishing this programmed cell death pathway as a critical nexus in inflammatory pathogenesis and tumor immunomodulation. This molecular crosstalk highlights PANoptosis as a promising therapeutic target for managing immune-related disorders and malignant transformation. Emerging evidence links PANoptosis to neuroinflammatory disorders through dysregulated crosstalk between programmed death pathways (apoptosis, necroptosis, pyroptosis) and accidental necrosis, driving neuronal loss and neural damage. Single-cell transcriptomics reveals spatially resolved PANoptosis signatures in Alzheimer's hippocampal microenvironments and multiple sclerosis demyelinating plaques, with distinct molecular clusters correlating to quantifiable neuroinflammatory metrics. Emerging PANoptosis-targeted therapies show preclinical promise in alleviating neurovascular dysfunction while preserving physiological microglial surveillance functions. Accumulating evidence linking dysregulated cell death pathways (particularly PANoptosis) to neurological disorders underscores the urgency of deciphering its molecular mechanisms and developing precision modulators as next-generation therapies. This review systematically deciphers PANoptosome assembly mechanisms and associated cell death cascades, evaluates their pathological roles in neurological disorders through multiscale regulatory networks, and proposes PANoptosis-targeted therapeutic frameworks to advance precision neurology.

Neuroinflammation is a pivotal factor in the progression of both age-related and acute neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Mitochondria, essential for neuronal health due to their roles in energy production, calcium buffering, and oxidative stress regulation, become increasingly susceptible to dysfunction under conditions of metabolic stress, aging, or injury. Impaired mitophagy in aged or injured neurons leads to the accumulation of dysfunctional mitochondria, which release mitochondrial-derived damage-associated molecular patterns (mtDAMPs). These mtDAMPs act as immune checkpoints, activating pattern recognition receptors (PRRs) and triggering innate immune signaling pathways. This activation initiates inflammatory responses in neurons and brain-resident immune cells, releasing cytokines and chemokines that damage adjacent healthy neurons and recruit peripheral immune cells, further amplifying neuroinflammation and neurodegeneration. Long-term mitochondrial dysfunction perpetuates a chronic inflammatory state, exacerbating neuronal injury and contributing additional immunogenic components to the extracellular environment. Emerging evidence highlights the critical role of mtDAMPs in initiating and sustaining neuroinflammation, with circulating levels of these molecules potentially serving as biomarkers for disease progression. This review explores the mechanisms of mtDAMP release due to mitochondrial dysfunction, their interaction with PRRs, and the subsequent activation of inflammatory pathways. We also discuss the role of mtDAMP-triggered innate immune responses in exacerbating both acute and chronic neuroinflammation and neurodegeneration. Targeting dysfunctional mitochondria and mtDAMPs with pharmacological agents presents a promising strategy for mitigating the initiation and progression of neuropathological conditions.

Necroptosis has been shown to play an important role in various pathologies, including pancreatic cancer (PDAC). However, its role in the progression of oral cancer (OSCC) remains unclear.

To determine the expression of key necroptosis pathway markers in an OSCC mouse model and evaluate the therapeutic effect of a necroptosis inhibitor on the progression of OSCC.

4-NQO-induced OSCC in mice resembles very closely to human OSCC. The expression of RIPK-1, RIPK-3, MLKL and their respective phosphorylation was increased in OSCC tissues of cancer-bearing mice. In the analysis of the necroptosis pathway in human OSCC with the TCGA database, we found similar overexpression of RIPK-1 in human cancer, which correlated with the severity of cancer in terms of different cancer grades and stages. Pharmacological blockade of necroptosis with necrostatin-1 (NEC-1) reduced the progression and development of OSCC, characterized by reduced number and severity of tumour lesions, improved histology with reduced hyperplasia, dysplasia and invasive carcinoma. Immune profiling of blood, spleen and tumour tissues demonstrated suppressed expression of MDSCs (CD11b+Gr-1+) and M2-macrophages (CD11b+F4/80+CD206+), while M1-macrophages (CD11b+F4/80+MHCII+) were elevated in the treatment group. The ratio of M2/M1 was reduced in the treated group, suggesting the promotion of anti-tumour immune response. Expression of Arg-1, YM1/2, IL-10 and TGF-β was reduced in tumour tissues in the treated group.

In summary, blocking the necroptosis pathway alters the tumour microenvironment (TME) and inhibits the progression of OSCC. Targeting necroptosis could be an effective therapy for treating OSCC in a clinical setup.

Reactive oxygen species (ROS) constitutes a group of reactive molecules that play a critical role in biological processes. Varying ROS levels have been frequently observed in cancer cells and the tumor microenvironment (TME). The role of ROS displays significant complexity in cancer development and therapy. Elevated ROS levels can induce metabolic reprogramming and promote the proliferation, invasion, and metastasis of cancer cells, resulting in cancer progression. However, excessive ROS accumulation leads to the occurrence of apoptosis, pyroptosis, necroptosis, and ferroptosis in cancer cells, which restrains tumor development. In the TME, ROS frequently promotes angiogenesis and remodels the extracellular matrix (ECM) by enhancing the differentiation of cancer-associated fibroblasts (CAFs), thereby supporting tumor growth. Concurrently, high ROS levels favour immunosuppressive cells, including M2-polarized macrophages, and regulatory T cells (Tregs), while impairing the antitumor capabilities of T cells. In the aspect of cancer therapy, it is overly simplistic to merely combine chemoradiotherapy with antioxidants as a therapeutic strategy. Instead, highlighting targeted therapies that modulate ROS is essential, given their inherent complexity. Fortunately, a variety of innovative treatments have emerged, including nanodrug delivery systems (NDDS), proteolysis-targeting chimeras (PROTAC), and adoptive cell therapy (ADT), which not only exhibit synergistic effects with immune checkpoint therapy (ICT), but also enhance the antitumor capabilities of the TME. In this paper, we elucidate the mechanism of ROS production, enumerate the role of ROS in cancer development and the TME, and discuss advancements in ROS-targeted cancer therapeutics.

Intervertebral disc degeneration (IDD) is a prevalent and debilitating spinal condition, characterised by the progressive degradation of disc structure and function, often accompanied by pain. Despite our increasing understanding of IDD, the precise mechanisms underlying its development and potential therapeutic targets remain incompletely understood. Recent research has highlighted that oxidative stress, along with immune abnormalities, mechanical loading imbalances, and metabolic disruptions, play a pivotal role in IDD initiation and progression. Oxidative stress in IDD results from an overproduction of reactive oxygen species (ROS) and a compromised ability to eliminate them, disrupting the redox homeostasis within the intervertebral disc. This disturbance in redox balance leads to extracellular matrix degradation (ECM), induces cellular apoptosis, and worsens the damage to disc tissues. This review provides a comprehensive overview of the pathophysiological processes of IDD, with a particular focus on the role of oxidative stress. Additionally, we explore current advancements in therapeutic strategies targeting oxidative stress, including antioxidant drugs, biomaterials, and stem cell-based approaches, offering promising avenues for the management and treatment of IDD.

Parkinson's disease (PD) is a movement disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). Recent studies have shown that necroptosis is involved in the development of inflammatory and neurodegenerative diseases. Receptor-interacting protein kinase (RIPK)1, RIPK3, and mixed lineage kinase domain-like protein (MLKL) play key roles in necroptosis, with MLKL being the final executor of necroptosis. Necrosulfonamide (NSA) is a specific inhibitor of MLKL, and its therapeutic effects in various inflammatory and neurological disorders have been previously reported. However, its role in PD has not yet been clearly demonstrated. In this study, we examined the effects of NSA in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. NSA reduced dopaminergic cell death and restored the expression of neurotrophic factors, such as BDNF, GDNF, and PGC-1α, in the SN region of MPTP mice. In addition, NSA inhibited microglial/astrocyte activation and the expression of proinflammatory markers, such as iNOS, TNF-α, IL-1β, and IL-6. NSA also reduced oxidative stress markers, such as 8-OHdG and 4-HNE, while enhancing Nrf2-driven antioxidant enzymes, including HO-1, catalase, MnSOD, GCLC, and GCLM. We found that NSA inhibited MLKL phosphorylation in dopaminergic neurons and microglia, which may have reduced neuronal cell death and inflammation. Therefore, NSA-mediated suppression of dopaminergic neuronal cell death, inflammation, and oxidative stress may have therapeutic potential in PD.

Reactive oxygen species (ROS), a class of highly reactive molecules, are closely linked to the pathogenesis of various cancers. While ROS primarily originate from normal cellular processes, external stimuli can also contribute to their production. Cancer cells typically exhibit elevated ROS levels due to disrupted redox homeostasis, characterized by an imbalance between antioxidant and oxidant species. ROS play a dual role in cancer biology: at moderate levels, they facilitate tumor progression by regulating oncogenes and tumor suppressor genes, inducing mutations, promoting proliferation, extracellular matrix remodeling, invasion, immune modulation, and angiogenesis. However, excessive ROS levels can cause cellular damage and initiate apoptosis, necroptosis, or ferroptosis.

This review explores molecular targets involved in redox homeostasis dysregulation and examines the impact of ROS on the tumor microenvironment (TME). Literature from recent in vitro and in vivo studies was analyzed to assess how ROS modulation contributes to cancer development and therapy.

Findings indicate that ROS influence cancer progression through various pathways and cellular mechanisms. Targeting ROS synthesis or enhancing ROS accumulation in tumor cells has shown promising anticancer effects. These therapeutic strategies exhibit significant potential to impair tumor growth while also interacting with elements of the TME.

The ROS serve as both promoters and suppressors of cancer depending on their intracellular concentration. Their complex role offers valuable opportunities for targeted cancer therapies. While challenges remain in precisely modulating ROS for therapeutic benefit, they hold promise as synergistic agents alongside conventional treatments, opening new avenues in cancer management.

Mitochondrial homeostasis is essential for cell survival and function, necessitating quality control mechanisms to ensure a healthy mitochondrial network. Death-associated protein 3 (DAP3) serves as a subunit of the mitochondrial ribosome, playing a pivotal role in the translation of mitochondrial-encoded proteins. Apart from its involvement in protein synthesis, DAP3 has been implicated in the process of cell death and mitochondrial dynamics. In this study, we demonstrate that DAP3 mediates cell death via intrinsic apoptosis by triggering excessive mitochondrial fragmentation, loss of mitochondrial membrane potential (ΔΨm), ATP decline, and oxidative stress. Notably, DAP3 induces mitochondrial fragmentation through the Mitochondrial Rho GTPase 1 (Miro1), independently of the canonical fusion/fission machinery. Mechanistically, DAP3 promotes mitochondrial calcium accumulation through the MCU complex, leading to decreased cytosolic Ca2+ levels. This reduction in cytosolic Ca2+ is sensed by Miro1, which subsequently drives mitochondrial fragmentation. Depletion of Miro1 or MCU alleviates mitochondrial fragmentation, oxidative stress, and cell death. Collectively, our findings reveal a novel function of the mitoribosomal protein DAP3 in regulating calcium signalling and maintaining mitochondrial homeostasis.

Inherited retinal diseases (IRDs) are a leading cause of blindness worldwide. One of the greatest barriers to developing treatments for IRDs is the heterogeneity of these disorders, with causative mutations identified in over 280 genes. It is therefore a priority to find therapies applicable to a broad range of genetic causes. To do so requires a greater understanding of the common or overlapping molecular pathways that lead to photoreceptor death in IRDs and the molecular processes through which they converge. Here, we characterise the contribution of different cell death mechanisms to photoreceptor degeneration and loss throughout disease progression in humanised mouse models of IRDs. Using single-cell transcriptomics, we identify common transcriptional signatures in degenerating photoreceptors. Further, we show that in genetically and functionally distinct IRD models, common early defects in autophagy and mitochondrial damage exist, triggering photoreceptor cell death by necroptosis in later disease stages. These results suggest that, regardless of the underlying genetic cause, these pathways likely contribute to cell death in IRDs. These insights provide potential therapeutic targets for novel, gene-agnostic treatments for IRDs applicable to the majority of patients.

The present study investigated the effects of antioxidant supplementation on the transcriptomic profiles of Hanwoo cattle during a 7-month feeding trial.

Twelve castrated Hanwoo cattle were randomly assigned to two groups: a control group (CON) and a group supplemented with antioxidants (FEED), consisting of vitamin C, vitamin E, and selenium. Growth performance and carcass traits were evaluated, and liver transcriptomic changes were assessed using RNA sequencing.

While no significant differences were observed in phenotypic traits such as weight gain and feed conversion ratio, transcriptomic analysis identified 641 differentially expressed genes between the CON and FEED groups. Functional enrichment analysis revealed that differentially expressed genes were mainly associated with transcription regulation, pseudouridine synthesis, and mitochondrial function. These findings suggest that antioxidant supplementation elicits significant molecular changes in the liver, particularly affecting transcriptional activity and mitochondrial processes, even in the absence of detectable phenotypic differences.

The development of phototherapeutics with high photothermal conversion efficiency (PCE) and strong ability to generate reactive oxygen species under single near-infrared (NIR) laser irradiation for immuno-phototherapy applications remains a significant challenge. Herein, we optimally selected the molecule IT-4 F with an acceptor-donor-acceptor (A-D-A) strucssture to prepare water-dispersible nanoparticles (NPs) by assembly with DSPE-PEG-NH2. Such NPs have NIR absorption and fluorescence peaks at 728 and 817 nm, respectively. They can generate singlet oxygen (1O2) and superoxide anion (O2-·) under laser irradiation, with a 1O2 generation quantum yield of 31.5%. They can also effectively convert photon-energy into heat with a high PCE of 42.8%. The outstanding properties of IT-4 F NPs enable them to be used in NIR fluorescence imaging guided photothermal therapy (PTT), and photodynamic therapy (PDT). Moreover, PDT and PTT triggered immunogenic cell death and PANoptosis in tumor cells, which not only inhibited tumor growth and metastasis in mice model, but also induced a robust immune response, evidenced by increased infiltration of CD8+ T cells, CD4+ T cells, dendritic cells, and a decreased presence of immunosuppressive cells such as myeloid-derived suppressor cells and regulatory T cells. The efficacy of IT-4 F NPs in organoid of human breast cancer was also verified.

Due to changes in dietary structures, population aging, and the exacerbation of metabolic risk factors, the incidence of cardiovascular disease continues to rise annually, posing a significant health burden worldwide. Cell death plays a crucial role in the onset and progression of cardiovascular diseases. As a regulated endpoint encountered by cells under adverse stress conditions, the execution of necroptosis is regulated by classicalpathways, the calmodulin-dependent protein kinases (CaMK) pathway, and mitochondria-dependent pathways, and implicated in various cardiovascular diseases, including atherosclerosis, myocardial infarction, myocardial ischemia-reperfusion injury (IRI), heart failure, diabetic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, chemotherapy drug-induced cardiomyopathy, and abdominal aortic aneurysm (AAA). To further investigate potential therapeutic targets for cardiovascular diseases, we also analyzed the main molecules and their inhibitors involved in necroptosis in an effort to uncover insights for treatment.

The discovery of ferroptosis has brought a revolutionary breakthrough in heart failure treatment, and natural products, as a significant source of drug discovery, are gradually demonstrating their extraordinary potential in regulating ferroptosis and alleviating heart failure symptoms. In addition to chemically synthesized small molecule compounds, natural products have attracted attention as an important source for discovering compounds that target ferroptosis in treating heart failure.

Systematically summarize and analyze the research progress on improving heart failure through natural products' modulation of the ferroptosis pathway.

By comprehensively searching authoritative databases like PubMed, Web of Science, and China National Knowledge Infrastructure with keywords such as "heart failure", "cardiovascular disease", "heart disease", "ferroptosis", "natural products", "active compounds", "traditional Chinese medicine formulas", "traditional Chinese medicine", and "acupuncture", we aim to systematically review the mechanism of ferroptosis and its link with heart failure. We also want to explore natural small-molecule compounds, traditional Chinese medicine formulas, and acupuncture therapies that can inhibit ferroptosis to improve heart failure.

In this review, we not only trace the evolution of the concept of ferroptosis and clearly distinguish it from other forms of cell death but also establish a comprehensive theoretical framework encompassing core mechanisms such as iron overload and system xc-/GSH/GPX4 imbalance, along with multiple auxiliary pathways. On this basis, we innovatively link ferroptosis with various types of heart failure, covering classic heart failure types and extending our research to pre-heart failure conditions such as arrhythmia and aortic aneurysm, providing new insights for early intervention in heart failure. Importantly, this article systematically integrates multiple strategies of natural products for interfering with ferroptosis, ranging from monomeric compounds and bioactive components to crude extracts and further to traditional Chinese medicine formulae. In addition, non-pharmacological means such as acupuncture are also included.

This study fills the gap in the systematic description of the relationship between ferroptosis and heart failure and the therapeutic strategies of natural products, aiming to provide patients with more diverse treatment options and promote the development of the heart failure treatment field.

Depression is a common mental health issue that can lead to various physical and psychological diseases. However, the relationship between depressive symptoms and premature death remains unclear.

In this study, we used data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 to assess the relationship between depressive symptoms and premature mortality and the potential influence of mitochondrial function on this relationship. The Patient Health Questionnaire-9 (PHQ-9) was used to assess the severity of depressive symptoms. Mortality data were obtained from the National Death Index (NDI). Mitochondrial function was assessed by measuring methylmalonic acid (MMA) levels. Multivariate logistic regression was used to assess the association between depressive symptoms and premature mortality, controlling for demographic, lifestyle, and disease-related factors. Restricted cubic splines were plotted, and propensity score matching (PSM) was used to create balanced groups. Finally, mediation analysis was performed to investigate the mediating role of MMA in the association between depressive symptoms and premature mortality.

This study included a total of 6599 participants. The results showed a substantial positive association (odds ratio [OR] = 1.452; 95 % confidence interval [CI], 1.038-2.031; p < 0.05) between depressive symptoms and premature mortality. The significance of this relationship was maintained after PSM analysis (OR = 2.370; 95 % CI, 1.749-3.212; p < 0.01). Mediation analysis showed that MMA partially mediated this relationship, with a mediation proportion of 4.1 %.

This study indicates that depressive symptoms significantly increases the risk of premature death and mitochondrial dysfunction partially mediates this positive relationship. Additional prospective and experimental studies are warranted to verify these findings.

Liver cancer is one of the most lethal cancers, and apoptosis resistance is a major obstacle contributing to chemotherapy failure in liver cancer treatment. Inducing cancer cell death by bypassing the apoptotic pathway is considered a promising approach to overcome this problem. Necroptosis is a non-caspase-dependent regulated mode of cell death mainly mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) protein, and the utilization of necroptosis for treating hepatocellular carcinoma (HCC) also offers a new hope for addressing liver cancer in the clinic. In this paper, the role of necroptosis in HCC as well as the effect on differentiation of liver cancer are reviewed. We also comparatively analyze the relationship among necroptosis, apoptosis, and necrosis, as well as summarize the characteristics and functions of key proteins involved in this pathway. The bidirectional regulation of necroptosis and the mitochondrial machinery within this pathway deserve attention.

Necroptosis, a distinct form of regulated necrosis implicated in various human pathologies, is orchestrated through sophisticated signaling pathways. During this process, cells undergoing necroptosis exhibit characteristic necrotic morphology and provoke substantial inflammatory responses. Post-translational modifications (PTMs)-chemical alterations occurring after protein synthesis that critically regulate protein functionality-constitute essential regulatory components within these complex signaling cascades. This intricate crosstalk between necroptotic pathways and PTM networks presents promising therapeutic opportunities. Our comprehensive review systematically analyzes the molecular mechanisms underlying necroptosis, with particular emphasis on the regulatory roles of PTMs in signal transduction. Through systematic evaluation of key modifications including ubiquitination, phosphorylation, glycosylation, methylation, acetylation, disulfide bond formation, caspase cleavage, nitrosylation, and SUMOylation, we examine potential therapeutic applications targeting necroptosis in disease pathogenesis. Furthermore, we synthesize current pharmacological strategies for manipulating PTM-regulated necroptosis, offering novel perspectives on clinical target development and therapeutic intervention.

Programmed cell death is a mechanism that is crucial for numerous physiological and pathological processes. Whereas p53-mediated apoptosis is a major cell death pathway in cancer, accumulating evidence indicates that p53 also has crucial roles in controlling different non-apoptotic cell death (NACD) pathways, including ferroptosis, necroptosis, pyroptosis, autophagy-dependent cell death, entotic cell death, parthanatos and paraptosis, and may regulate PANoptosis, cuproptosis and disulfidptosis. Notably, the function of p53 in these NACDs substantially contributes to its biological effects, particularly in cancer development and other pathological processes. In this Review, we discuss recent advances in understanding the roles and underlying mechanisms of p53-mediated NACDs, focusing on ferroptosis, necroptosis and pyroptosis. We discuss the complex and distinct physiological settings in which NACDs are regulated by p53, and potential targeting of p53-regulated NACDs for the treatment of cancer and other human diseases. Finally, we highlight several important questions concerning p53-regulated NACDs that warrant further investigation.

Edaravone (Eda), a well-known free radical scavenger, has been reported as a possible therapeutic agent for ischemic stroke patients' recovery. This study aimed to investigate the effects of time-dependent treatment with Eda on medial prefrontal cortex (mPFC) ischemia. Mice were randomly allocated into six groups: control, sham, normal saline, Eda-I, Eda-II, and Eda-III. After induction of a photothrombotic ischemia in the mPFC region, Eda-I, Eda-II, and Eda-III groups received 3 mg/kg Eda intraperitoneally at the times of 0, 2, and 6 h post-surgery. After 1 day of recovery, the mice underwent behavioral tests (open field, novel object recognition, and T-maze). Next, necroptosis, NOD-like receptor protein 3 (NLRP3), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway-related protein levels were measured in the lesioned area using western blot analysis. For double confirmation, IL-1β and IL-18 were also assessed by immunofluorescence in the area. Further, histological evaluations were performed to measure tissue damage. The results showed that mPFC ischemia impaired recognition and spatial working memory without affecting locomotor activity, while immediate Eda administration improved cognitive impairments. Furthermore, acute Eda treatment reduced RIP1, RIP3, and MLKL levels, inhibited NLRP3 inflammasome proteins (NLRP3, ASC, and Cas1), decreased IL-1β and IL-18, upregulated Nrf2 and its targets (NQO-1 and HO-1), and diminished tissue damage. Our results highlighted the effects of acute administration of Eda post-stroke on improving cognitive impairments by suppressing necroptosis and NLRP3 inflammasome pathways and activating the Nrf2 antioxidant defense mechanism.

This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.

Hepatocellular carcinoma (HCC), the most prominent type of primary liver cancer, often diagnosed late, leading to poor prognosis and limited treatment options. This study investigated the anti-carcinogenic effect of Quinazoline-2,4(1H,3H)-dione (Qd), a quinazoline derivative of natural origin and identified Qd as an effective compound against HCC via STAT3 and FOXO3a signaling. STAT3 and FOXO3a are two well-known molecular drivers of HCC. In silico findings revealed Qd as the potent candidate due to its highly stable interaction with STAT3 and FOXO3a. To validate its anticancer activity, in vitro experiments were conducted on the HepG2 cell line. Qd exerts cytotoxic effect in HepG2 cells with an IC50 value of 26.07 μM, while being non-toxic in WRL-68 cells at a lower concentrations with an IC50 of 326.5 μM. Morphological changes and apoptotic cell death were confirmed using DAPI staining and Live/Dead assay. Qd also induced ROS-mediated mitochondrial damage. Qd upregulated mRNA expressions of pro-apoptotic and necroptotic markers while downregulating anti-apoptotic marker. Accordingly, the protein expression analysis demonstrated increased levels of Bax, Caspase 3, c-PARP, RIPK1, RIPK3 and MLKL, while decreasing Bcl2 and PARP expressions. Gene and protein expression of STAT3 remained at a basal level while FOXO3a gene expression increased significantly at 5 μM Qd concentration. Significant changes were particularly observed at 5 μM Qd concentration in all in vitro experiments. Despite quinazoline compounds have been shown biological and pharmacological effects, the anticancer effect of Qd is elusive till date. These in silico and in vitro findings highlighted Qd as a potent compound for further exploration in HCC therapy by targeting apoptotic and necroptotic cell death pathways.

Hemoglobin (Hb) and heme, which are typically confined within red blood cells (RBCs), are essential for intravascular transport of gases and nutrients. However, these molecules acquire secondary functions upon exposure to the extracellular environment. Hb and heme generate reactive oxygen species (ROS), which are potent pro-inflammatory agents that contribute to oxidative stress and cellular damage. These events are relevant to neurodegenerative processes, where oxidative stress, irregular deposition of protein aggregates, and chronic inflammation are key pathological features. Extracellular Hb, heme, and oxidative stress derived from hemorrhagic events or RBC lysis may contribute to increased blood-brain barrier (BBB) permeability. These events allow Hb and heme to interact with neuroimmune cells and pathological protein aggregates, further amplifying pro-inflammatory signaling and the progression of Alzheimer's disease (AD) and Parkinson disease (PD). Chronic neuroinflammation, oxidative stress, and mitochondrial dysfunction lead to neuronal degeneration. Here, we sought to elucidate the pro-oxidative and inflammatory actions of extracellular Hb and heme, emphasizing their potential impact on AD and PD development.

Gestational diabetes mellitus (GDM) is diabetes with reduced glucose tolerance that is found or diagnosed during pregnancy, which seriously affects the health of mothers and infants, and its incidence is increasing year by year. The necroptotic apoptosis regulator RIP3 has been proposed to be active in managing pancreatic islet cell survival and inflammatory response. Still, its role and mechanism in GDM have not yet been clarified.

The effect of high glucose induction and RIP3 on the viability of Pancreatic β-cells and insulin secretion was observed in vitro experiments. C57BL/6J mice were used to establish the GDM model. Weight, serum glucose levels, and insulin levels were measured to evaluate the improvement of diabetes symptoms in GDM mice by sh-RIP3. The levels of IL-1β, IL-6, and TNF-α were determined by ELISA and qRT-PCR assays. Hematoxylin and Eosin (HE) staining assay was applied to detect islet cell morphology and inflammatory damage in pancreatic tissue. Progeny weight and litter size were also recorded to evaluate reproductive function in GDM mice. Western blot was performed to express TLR4/MyD88/NF-κB signal-related proteins.

Knockdown of RIP3 ameliorated GDM symptoms, improved glucose tolerance and insulin sensitivity, suppressed inflammation, and enhanced fetal outcomes, possibly by TLR4/MyD88/NF-κB signaling pathway activation in GDM mice.

The present study provided evidence that the downregulation of RIP3 alleviates insulin resistance and inflammation in GDM mice by mediating the TLR4/MyD88/NF-κB signaling pathway, which made RIP3 a new potential therapeutic target for GDM treatment in the future.

Necroptosis is a programmed form of cell death. Receptor-interacting serine/threonine protein kinase l (RIPK1) is a crucial protein kinase that regulates the necroptosis pathway. Increased expression of death receptor family ligands such as tumor necrosis factor (TNF) increases the susceptibility of cells to apoptosis and necroptosis. RIPK1, RIPK3, and mixed-lineage kinase-like domain (MLKL) proteins mediate necrosis. RIPK1-mediated necroptosis further promotes cell death and inflammation in the pathogenesis of liver injury, skin diseases, and neurodegenerative diseases. The N-terminal kinase domain of RIPK1 is significant in the induction of cell death and can be used as a vital drug target for inhibitors. In this paper, we outline the pathways of necroptosis and the role RIPK1 plays in them and suggest that targeting RIPK1 in therapy may help to inhibit multiple cell death pathways.

The phenomenon of cell death has garnered significant scientific attention in recent years, emerging as a pivotal area of research. Recently, novel modalities of cellular death and the intricate interplay between them have been unveiled, offering insights into the pathogenesis of various diseases. This comprehensive review delves into the intricate molecular mechanisms, inducers, and inhibitors of the underlying prevalent forms of cell death, including apoptosis, autophagy, ferroptosis, necroptosis, mitophagy, and pyroptosis. Moreover, it elucidates the crosstalk and interconnection among the key pathways or molecular entities associated with these pathways, thereby paving the way for the identification of novel therapeutic targets, disease management strategies, and drug repurposing.

Tetrabromobisphenol A (TBBPA) is an aquatic environment's prevalent pollutant, posing a great threat to the health of aquatic animals. The intestine is a key organ for nutrient absorption as well as an important barrier to prevent pollutants from invading the body of fish. Exploring the effects of pollutants on the intestine is of great significance for maintaining fish health. Therefore, the purpose of this study was to assess the toxic effects of TBBPA on the intestine of Cyprinus carpio L. (common carp) by establishing models of common carp and primary intestinal epithelial cells exposed to TBBPA. Histological observation revealed that TBBPA exposure led to damage in the intestinal mucosa and breakage of intestinal villi. Detection of oxidative stress levels showed that TBBPA increased the levels of ROS and MDA, and decreased the activity of SOD, CAT, GSH-PX, and T-AOC in intestinal tissue and cells. Observation of inflammatory factor levels revealed that TBBPA upregulated the mRNA levels of inflammatory factors (IL-6, TNF-α, IL-1β, NF-κB p65 and IκBα). ELISA and western blotting results were consistent with the mRNA results. Moreover, TBBPA induced cell death, as evidenced by TUNEL staining and flow cytometry and confirmed by increasing levels of Bax, Cas-3, Cyt C, RIP1, RIP3, and MLKL, together with decreasing the levels of Bcl-2. TBBPA also destroyed the intestinal tight junction by reducing the mRNA and protein levels of claudin-1, ZO-1, and occludin. In summary, this study reveals that TBBPA caused intestinal injuries, inducing oxidative stress, inflammation, cell death, and tight junction disruption via ROS/NF-κB signal in common carp.

Obesity is an exceedingly prevalent and frequent health issue in today's society. Fat deposition is accompanied by low-grade inflammation in fat tissue and throughout the body, leading to metabolic disorders that ultimately promote the onset of obesity-related diseases. The development of obesity is accompanied by cell death events such as apoptosis as well as pyroptosis, however, the role of necroptosis in obesity has been widely reported in recent years. Necroptosis, a mode of cell death distinct from apoptosis and necrosis, is associated with developing many inflammatory conditions and their associated diseases. It also exhibits modulation of apoptosis and pyroptosis. It is morphologically similar to necroptosis, characterized by the inhibition of caspase-8, the formation of membrane pores, and the subsequent rupture of the plasma membrane. This paper focuses on the key pathways and molecules of necroptosis, exploring its connections with apoptosis and pyroptosis, and its implications in obesity. This paper posits that the modulation of necroptosis-related targets may represent a novel potential therapeutic avenue for the prevention and treatment of obesity-induced systemic inflammatory responses, and provides a synopsis of potential molecular targets that may prove beneficial in obesity-associated inflammatory diseases.

Vascular dementia (VaD) includes a group of brain disorders that are characterized by cerebrovascular pathology.Neuroinflammation, disruption of the blood-brain barrier (BBB) permeability, white matter lesions, and neuronal loss are all significant pathological manifestations of VaD and play a key role in disease progression. Necroptosis, also known asprogrammed necrosis, is a mode of programmed cell death distinct from apoptosis and is closely associated with ischemic injury and neurodegenerative diseases. Recent studies have shown that necroptosis in VaD exacerbates BBB destruction, activates neuroinflammation, promotes neuronal loss, and severely affects VaD prognosis.

In this review, we outline the significant roles of necroptosis and its molecular mechanisms in the pathological process of VaD, with a particular focus on the role of necroptosis in modulating neuroinflammation and exacerbating the disruption of BBB permeability in VaD, and elaborate on the molecular regulatory mechanisms and the centrally involved cells of necroptosis mediated by tumor necrosis factor-α in neuroinflammation in VaD. We also analyze the possibility and specific strategy that targeting necroptosis would help inhibit neuroinflammation and BBB destruction in VaD. With a focus on necroptosis, this study delved into its impact on the pathological changes and prognosis of VaD to provide new treatment ideas.

Background/Objectives: Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) are rare but severe skin conditions, often triggered by medications, that can be life-threatening. These conditions frequently affect the eyes, causing ocular surface disease, which can result in visual impairment or blindness. Although the exact mechanisms behind SJS/TEN remain unclear, key inflammatory mediators such as IL-1β, IL-6, and RIPK3 are believed to play critical roles in inflammation, necroptosis, and regulatory processes. Investigating these factors offers new insights into the disease's underlying mechanisms and potential targets for treatment. This study aims to determine the roles of IL-1β, IL-6, and RIPK3 in the pathogenesis of SJS/TEN. Methods: The study examined the expression levels of IL-1β, IL-6, and RIPK3 in skin biopsies from patients with biopsy-confirmed SJS/TEN, using lichen planus as a positive control and normal skin as a baseline control. Immunohistochemistry was employed for this analysis. Additionally, the impact of SJS/TEN patient plasma on mitochondrial function was assessed in platelets and human corneal epithelial (H-CET) cells. Using a fluorescent plate reader, mitochondrial activity and superoxide ion levels were measured, comparing plasma from SJS/TEN patients to normal human plasma. Results: Skin biopsies from SJS/TEN patients showed a significantly higher expression of IL-1β, IL-6, and RIPK3 compared to both lichen planus and normal controls. Furthermore, plasma from SJS/TEN patients significantly reduced platelet viability and increased mitochondrial and total cellular superoxide ions, as demonstrated by elevated levels of MitoSOX Red and CellROX Red. Conclusions: These findings suggest that IL-1β, IL-6, and RIPK3 may contribute to the pathogenesis of SJS/TEN and highlight their potential as targets for therapeutic intervention.

Sepsis is a life-threatening condition resulting from pathogen infection and characterized by organ dysfunction. Programmed cell death (PCD) during sepsis has been associated with the development of multiple organ dysfunction syndrome (MODS), impacting various physiological systems including respiratory, cardiovascular, renal, neurological, hematological, hepatic, and intestinal systems. It is well-established that pathogen infections lead to immune dysregulation, which subsequently contributes to MODS in sepsis. However, recent evidence suggests that sepsis-related opportunistic pathogens can directly induce organ failure by promoting PCD in parenchymal cells of each affected organ. This study provides an overview of PCD in damaged organ and the induction of PCD in host parenchymal cells by opportunistic pathogens, proposing innovative strategies for preventing organ failure in sepsis.

Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory disease worldwide. Mitochondrial quality control mechanisms encompass processes such as mitochondrial biogenesis, fusion, fission, and autophagy, which collectively maintain the quantity, morphology, and function of mitochondria, ensuring cellular energy supply and the progression of normal physiological activities. However, in COPD, due to the persistent stimulation of harmful factors such as smoking and air pollution, mitochondrial quality control mechanisms often become deregulated, leading to mitochondrial dysfunction. Mitochondrial dysfunction plays a pivotal role in the pathogenesis of COPD, contributing toinflammatory response, oxidative stress, cellular senescence. However, therapeutic strategies targeting mitochondria remain underexplored. This review highlights recent advances in mitochondrial dysfunction in COPD, focusing on the role of mitochondrial quality control mechanisms and their dysregulation in disease progression. We emphasize the significance of mitochondria in the pathophysiological processes of COPD and explore potential strategies to regulate mitochondrial quality and improve mitochondrial function through mitochondrial interventions, aiming to treat COPD effectively. Additionally, we analyze the limitations and challenges of existing therapeutic strategies, aiming to provide new insights and methods for COPD treatment.

Acute myocardial infarction (MI) is a leading cause of death worldwide. Although with current treatment, acute mortality from MI is low, the damage and remodeling associated with MI are responsible for subsequent heart failure. Reducing cell death associated with acute MI would decrease the mortality associated with heart failure. Despite considerable study, the precise mechanism by which ischemia and reperfusion (I/R) trigger cell death is still not fully understood. In this Review, we summarize the changes that occur during I/R injury, with emphasis on those that might initiate cell death, such as calcium overload and oxidative stress. We review cell-death pathways and pathway crosstalk and discuss cardioprotective approaches in order to provide insight into mechanisms that could be targeted with therapeutic interventions. Finally, we review cardioprotective clinical trials, with a focus on possible reasons why they were not successful. Cardioprotection has largely focused on inhibiting a single cell-death pathway or one death-trigger mechanism (calcium or ROS). In treatment of other diseases, such as cancer, the benefit of targeting multiple pathways with a "drug cocktail" approach has been demonstrated. Given the crosstalk between cell-death pathways, targeting multiple cardiac death mechanisms should be considered.

Approximately one-tenth of the global population is affected by diabetes mellitus, and its incidence continues to rise each year. In China, 1.4 million patients die from diabetes-related complications every year. Additionally, approximately 26% of patients with diabetes develop diabetic cardiomyopathy, with heart failure being one of the main causes of death in these patients. However, early detection of diabetic cardiomyopathy has proven to be difficult in a clinical setting; furthermore, there are limited guidelines and targeted means of prevention and treatment for this disease. In recent years, several studies have provided evidence for the occurrence of various forms of regulated cell death in diabetic myocardial cells, including apoptosis, necroptosis, ferroptosis, and cuproptosis, which are closely linked to the pathological progression of diabetic cardiomyopathy. Although most research on diabetic cardiomyopathy is currently in the animal trial phase, the inhibition of these regulatory cell death processes can limit or slow down the progression of diabetic cardiomyopathy. Therefore, this review discusses the appropriate animal experimental models currently available for diabetic cardiomyopathy and evaluates the roles of apoptosis, necroptosis, ferroptosis, and cuproptosis in diabetic cardiomyopathy. We hope to provide new methods and ideas for future research in diabetic cardiomyopathy.

Leprosy, caused by Mycobacterium leprae (M. leprae), is a chronic infectious disease primarily affecting the skin and peripheral nerves. The interaction between M. leprae and macrophages, its primary host cell, plays a critical role in disease progression. This review explores the various forms of macrophage cell death induced by M. leprae infection, including apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis and necrosis. The regulation and implications of these cell death pathways on the host immune response are discussed. Apoptosis and autophagy are highlighted as mechanisms that may limit M. leprae proliferation, while necroptosis and pyroptosis contribute to inflammation and immune response. Notably, recent studies have identified CYBB-mediated ferroptosis as essential for macrophages infected with M. leprae to polarize towards the M2 phenotype, facilitating immune evasion by the pathogen. This review underscores the complexity of macrophage cell death in leprosy, and summarize their corresponding molecular mechanisms and potential impact on the host immunity.

Necroptosis is considered a programmed necrosis that requires receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and pore-forming mixed lineage kinase domain-like protein (MLKL) to trigger a regulated cell membrane lysis. Membrane rupture in necroptosis has been shown to fuel innate immune response due to release of damage-associated molecular patterns (DAMPs). Recently published studies indicate that mature erythrocytes can undergo necroptosis as well. In this review, we provide an outline of multiple cell death modes occurring in erythrocytes, discuss possible immunological aspects of diverse erythrocyte cell deaths, summarize available evidence related to the ability of erythrocytes to undergo necroptosis, outline key involved molecular mechanisms, and discuss the potential implication of erythrocyte necroptosis in the physiology and pathophysiology. Furthermore, we aim to highlight the interplay between necroptosis and eryptosis signaling in erythrocytes, emphasizing specific characteristics of these pathways distinct from their counterparts in nucleated cells. Thus, our review provides a comprehensive summary of the current knowledge of necroptosis in erythrocytes. To reflect critical differences between necroptosis of nucleated cells and necroptosis of erythrocytes, we suggest a term erythronecroptosis for necroptosis of enucleated cells.

Cell death is a fundamental part of life for metazoans. To maintain the balance between cell proliferation and metabolism of human bodies, a certain number of cells need to be removed regularly. Hence, the mechanisms of cell death have been preserved during the evolution of multicellular organisms. Tumorigenesis is closely related with exceptional inhibition of cell death. Mutations or defects in cell death-related genes block the elimination of abnormal cells and enhance the resistance of malignant cells to chemotherapy. Therefore, the investigation of cell death mechanisms enables the development of drugs that directly induce tumor cell death. In the guidelines updated by the Cell Death Nomenclature Committee (NCCD) in 2018, cell death was classified into 12 types according to morphological, biochemical and functional classification, including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, PARP-1 parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence and mitotic catastrophe. The mechanistic relationships between epigenetic controls and cell death in cancer progression were previously unclear. In this review, we will summarize the mechanisms of cell death pathways and corresponding epigenetic regulations. Also, we will explore the extensive interactions between these pathways and discuss the mechanisms of cell death in epigenetics which bring benefits to tumor therapy.

A shared hallmark of age-related neurodegenerative diseases is the chronic activation of innate immune cells, which actively contributes to the neurodegenerative process. In Alzheimer's disease, this inflammatory milieu exacerbates both amyloid and tau pathology. A similar abnormal inflammatory response has been reported in Parkinson's disease, with elevated levels of cytokines and other inflammatory intermediates derived from activated glial cells, which promote the progressive loss of nigral dopaminergic neurons. Understanding the causes that support this aberrant inflammatory response has become a topic of growing interest and research in neurodegeneration, with high translational potential. It has been postulated that the phenotypic shift of immune cells towards a proinflammatory state combined with the presence of immunogenic cell death fuels a vicious cycle in which mitochondrial dysfunction plays a central role. Mitochondria and mitochondria-generated reactive oxygen species are downstream effectors of different inflammatory signaling pathways, including inflammasomes. Dysfunctional mitochondria are also recognized as important producers of damage-associated molecular patterns, which can amplify the immune response. Here, we review the major findings highlighting the role of mitochondria as a checkpoint of neuroinflammation and immunogenic cell deaths in neurodegenerative diseases. The knowledge of these processes may help to find new druggable targets to modulate the inflammatory response.

Background: Resistance to standard therapeutic methods, including chemotherapy, immunotherapy, and targeted therapy, remains a critical challenge in effective cancer treatment. Redox homeostasis modification has emerged as a promising approach to address medication resistance. Objective: This review aims to explore the mechanisms of redox alterations and signaling pathways contributing to treatment resistance in cancer. Methods: In this study, a comprehensive review of the molecular mechanisms underlying drug resistance governed by redox signaling was conducted. Emphasis was placed on understanding how tumor cells manage increased reactive oxygen species (ROS) levels through upregulated antioxidant systems, enabling resistance across multiple therapeutic pathways. Results: Key mechanisms identified include alterations in drug efflux, target modifications, metabolic changes, enhanced DNA damage repair, stemness preservation, and tumor microenvironment remodeling. These pathways collectively facilitate tumor cells' adaptive response and resistance to various cancer treatments. Conclusion: Developing a detailed understanding of the interrelationships between these redox-regulated mechanisms and therapeutic resistance holds potential to improve treatment effectiveness, offering valuable insights for both fundamental and clinical cancer research. Antioxid. Redox Signal. 00, 000-000.

Addressing the inefficiency of current therapeutic approaches for hepatocellular carcinoma is an urgent and pressing challenge. PANoptosis, a form of inflammatory programmed cell death, presents a dependable strategy for combating cancer by engaging multiple cell death pathways (apoptosis, pyroptosis, and necroptosis). In this study, an ultrasmall Bi2Sn2O7 nanozyme with ultrasound-magnified multienzyme-mimicking properties is designed and engineered as a PANoptosis inducer through destroying the mitochondrial function of tumor cells and enhancing the intracellular accumulation of toxic reactive oxygen species, finally triggering the activation of PANoptosis process. The role of PANoptosis inducer has been verified by the expression of related proteins, including cleaved Caspase 3, NLRP3, N-GSDMD, cleaved Caspase 1, p-MLKL, and RIPK3. The inclusion of external ultrasonic irradiation significantly augments the enzyodynamic therapeutic efficiency. In vitro and in vivo antineoplastic efficacy, along with inhibition of lung metastasis, validate the benefits of the Bi2Sn2O7-mediated PANoptosis pathway. This study not only elucidates the intricate mechanisms underlying Bi2Sn2O7 as a PANoptosis inducer, but also offers a novel perspective for the treatment of hepatocellular carcinoma.

Mitochondria serve as the primary site for aerobic respiration within cells, playing a crucial role in maintaining cellular homeostasis. To maintain homeostasis and meet the diverse demands of the cells, mitochondria have evolved intricate systems of quality control, mainly including mitochondrial dynamics, mitochondrial autophagy (mitophagy) and mitochondrial biogenesis. The kidney, characterized by its high energy requirements, is particularly abundant in mitochondria. Interestingly, the mitochondria display complex behaviors and functions. When the kidney is suffered from obstructive, ischemic, hypoxic, oxidative, or metabolic insults, the dysfunctional mitochondrial derived from the defects in the mitochondrial quality control system contribute to cellular inflammation, cellular senescence, and cell death, posing a threat to the kidney. However, in addition to causing injury to the kidney in several cases, mitochondria also exhibit protective effect on the kidney. In recent years, accumulating evidence indicated that mitochondria play a crucial role in adaptive repair following kidney diseases caused by various etiologies. In this article, we comprehensively reviewed the current understanding about the multifaceted effects of mitochondria on kidney diseases and their therapeutic potential.