Neurodegenerative diseases (e.g., Alzheimer's, Parkinson's, Huntington's disease, and Amyotrophic Lateral Sclerosis) are major health threats for the aging population and their prevalences continue to rise with the increasing of life expectancy. Although progress has been made, there is still a lack of effective cures to date, and an in-depth understanding of the molecular and cellular mechanisms of these neurodegenerative diseases is imperative for drug development. Protein phosphorylation, regulated by protein kinases and protein phosphatases, participates in most cellular events, whereas aberrant phosphorylation manifests as a main cause of diseases. As evidenced by pharmacological and pathological studies, protein kinases are proven to be promising therapeutic targets for various diseases, such as cancers, central nervous system disorders, and cardiovascular diseases. The mechanisms of protein phosphatases in pathophysiology have been extensively reviewed, but a systematic summary of the role of protein kinases in the nervous system is lacking. Here, we focus on the involvement of protein kinases in neurodegenerative diseases, by summarizing the current knowledge on the major kinases and related regulatory signal transduction pathways implicated in diseases. We further discuss the role and complexity of kinase-kinase networks in the pathogenesis of neurodegenerative diseases, illustrate the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies (such as antisense oligonucleotides and gene therapy) for effective prevention and early intervention.

Oxysterol-binding proteins (OSBPs), lipid transfer proteins functioning at intracellular membrane contact sites, are recently found to be dysregulated in cancer and promote cancer cell survival. However, their role as potential targets in cancer therapy remains largely unexplored. In this study, we found OSW-1, a natural compound and OSBP inhibitor, potently and selectively kills colon cancer cells by activating a previously unknown necroptosis pathway that is independent of receptor-interacting protein 1 (RIP1) and RIP3. OSW-1 stabilizes p53 and degrades OSBPs to promote endoplasmic reticulum (ER) stress and glycogen synthase kinase 3β (GSK3β)/Tip60-mediated p53 acetylation at Lysine 120, which selectively induces its target PUMA. PUMA-mediated mitochondrial calcium influx activates calcium/calmodulin-dependent protein kinase IIδ (CamKIIδ) to promote mixed lineage kinase domain-like (MLKL) phosphorylation and necroptotic cell death. Furthermore, OSW-1-induced necroptosis is highly immunogenic and sensitizes syngeneic colorectal tumors to anti-PD-1 immunotherapy. Together, our results identified a novel RIP1/RIP3-independent necroptosis pathway underlying the extremely potent anticancer activity of OSW-1, which can be harnessed to develop new anticancer therapies by selectively stimulating antitumor immunity.

Encapsulated BV6 and SM164, two bivalent second mitochondria-derived activator of caspase (Smac) mimetics, in etoposide (ETO)-lipopolymer nanoparticles (NPs) have been developed to deplete inhibitor of apoptosis proteins (IAP), impair DNA, and produce antagonistic effects on glioblastoma multiforme (GBM) in nude mice. The NPs, composed of cocoa butter (CB) and polyvinyl alcohol (PVA), were stabilized by glycerol monostearate and Pluronic F-127, and grafted with transferrin (Tf) and wheat germ agglutinin (WGA) to dock the blood-brain barrier (BBB) and degenerated dopaminergic neurons. The dual-targeting NPs increased the BBB permeability of BV6, SM164 and ETO via recognizing Tf receptor (TfR) and N-acetylglucosamine that are abundantly expressed on brain microvascular endothelial cells. The sustained release of BV6, SM164 and ETO from CB-PVA-NPs for 48 h resulted in a reduction of about 40 % in the viability of U87MG cells and human brain cancer stem cells. Hematoxylin and eosin staining of the brain in GBM mice revealed atypical mitosis of cancer cells and a considerable decrease in tumor cell density after treatment with Tf-WGA-BV6-SM164-ETO-NPs. Compared to untreated mice, the current ETO preparation carrying Smac mimetics reduced cellular IAP-1 expression to about 33 % and X-linked IAP expression to about 42 %, while enhanced about 3.8-fold caspase-3, indicating the effectiveness of the nanocarriers in accelerating apoptosis of GBM cells. Tf-WGA-CB-PVA-NPs can be promising to upgrade BV6 and SM164 activity by ETO in clinical trials for GBM management.

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.

Ultraviolet B (UVB) is recognized for inducing inflammation and death of keratinocytes through the activation of death receptors and pattern recognition receptors (PRRs). Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 play pivotal roles in mediating necroptosis, which can be triggered by the activation of specific death receptors and PRRs. In this study, we observed a reduction of RIPK1 protein after UVB exposure which led to activation of Nuclear factor-kappa B (NF-κB) in HaCaT cells. This activation, in turn, promoted the production of IL-1β and TNF-α. However, RIPK1 kinase remained inactive and did not participate in cell death. Interestingly, UVB radiation triggered the activation of RIPK3 independently of RIPK1 kinase activity and subsequently induced phosphorylation of mixed-lineage kinase domain-like protein (MLKL), culminating in necroptosis and inflammation of the skin. At the same time, UVB-induced activation of RIPK3 also played a role in promoting the mitochondrial apoptotic pathway of Keratinocytes. In conclusion, UVB irradiation initiates an inflammatory response via RIPK1 pathway without necessitating its enzymatic activity. Simultaneously, RIPK3 can be activated by UVB exposure independently of RIPK1's activity, resulting in necroptosis and inflammation of the skin.

Neuroblastoma (NB) is the most typical malignant extracranial solid tumor in the pediatric population. The advent of drug resistance is an essential deterrent in treating high-risk NB patients despite a multi-modality remedy. Inflammation-induced early neuronal degeneration plays a leading part in the pathogenesis of NB via necroptosis; however, the mechanisms remained cryptic. Our current investigation determines the anti-inflammatory and neuroprotective effect of necroptosis inhibitor necrostatin-1 (Nec-1) in receptor-interacting proteins 1 and 3 (RIP1/3)-induced cell death pathway and inflammation caused by hypoxia mimetic agent cobalt chloride (CoCl2). Our biomolecular study illustrates that necroptosis marker RIP1/3 and mixed-lineage kinase domain-like pseudokinase (MLKL) protein expression was increased after treatment with CoCl2 in SH-SY5Y cells. Subsequently, elevated expression levels of RIP1/3 and MLKL further contributed to the inflammation by activating transcription factors extracellular signal-regulated protein kinase (ERK1/2), nuclear factor kappa-B (NF-κB), and releasing high levels of proinflammatory cytokines, such as vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1/CCL2). At the same time, Nec-1 treatment reduced the RIP1/3 and MLKL, phospho-ERK1/2, p65 subunit of NF-κB expression, and VEGF and MCP-1 levels. Molecular docking analysis of RIP1/3-necrostatin-1 complex highlights a significant interaction between necrostatin-1 and specific amino acid residues within the protein. Based on our promising results, necrostatin-1 could be exploited as a therapeutic agent during neuroblastoma's pathogenesis and its molecular therapy.

Dysfunctional NF-κB signaling is critically involved in inflammatory bowel disease (IBD). We investigated the mechanism by which RIPK1 and TRADD, two key mediators of NF-κB signaling, in mediating intestinal pathology using TAK1 IEC deficient model. We show that phosphorylation of TRADD by TAK1 modulates RIPK1-dependent apoptosis. TRADD and RIPK1 act cooperatively to mediate cell death regulated by TNF and TLR signaling. We demonstrate the pathological evolution from RIPK1-dependent ileitis to RIPK1- and TRADD-co-dependent colitis in TAK1 IEC deficient condition. Combined RIPK1 inhibition and TRADD knockout completely protect against intestinal pathology and lethality in TAK1 IEC KO mice. Furthermore, we identify distinctive microbiota dysbiosis biomarkers for RIPK1-dependent ileitis and TRADD-dependent colitis. These findings reveal the cooperation between RIPK1 and TRADD in mediating cell death and inflammation in IBD with NF-κB deficiency and suggest the possibility of combined inhibition of RIPK1 kinase and TRADD as a new therapeutic strategy for IBD.

In modern society, excessive nutrient intake from food is a major factor contributing to the development of a series of metabolic disorders and cardiovascular diseases. Further investigation of the mechanisms underlying nutrient absorption in the intestine will help to better understand and develop preventive or therapeutic strategies. In this study, using receptor-interacting protein kinase 1 (Ripk1) intestine-specific heterozygous knockout mice (Ripk1 IEC+/-) and high-fat diet (HFD)-feeding mouse model, we report that HFD-induced shift in the transcriptional profile of the ileum toward that of the jejunum, characterized by increased expression of jejunal feature genes in the ileum, are attenuated in Ripk1 IEC+/- female mice, but not in males. Accordingly, HFD-induced metabolic disorders, including obesity, impaired glucose tolerance, insulin resistance, and dyslipidemia, are significantly ameliorated in the Ripk1 IEC+/- female mice. These findings demonstrate a new, sex-specific intestinal regulatory mechanism and highlight the critical role of intestinal RIPK1 in regulating HFD-induced metabolic disorders in females.

Osteoarthritis (OA) is a common degenerative joint disease characterized by the progressive degradation of articular cartilage, synovial inflammation, and subchondral bone remodeling. This review explores the interplay between aging, PANoptosis, and inflammation in OA progression. Age-related cellular and immune dysfunctions, including cellular senescence, senescence-associated secretory phenotypes (SASPs), and immunosenescence, significantly contribute to joint degeneration. In OA, dysregulated apoptosis, necroptosis, and pyroptosis, particularly in chondrocytes, exacerbate cartilage damage. Apoptosis, mediated by the JNK pathway, reduces chondrocyte density, while necroptosis and pyroptosis, involving RIPK-1/RIPK-3 and the NLRP3 inflammasome, respectively, amplify inflammation and cartilage destruction. Inflammatory cytokines and damage-associated molecular patterns (DAMPs) further enhance these PANoptotic pathways. Current therapeutic strategies primarily focus on anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, with growing interest in anti-senescence drugs targeting cellular senescence and SASP. Additionally, exploring PANoptosis mechanisms offers potential for innovative OA treatments.

As a central hub for metabolism, the liver exhibits strong adaptability to maintain homeostasis in response to food fluctuations throughout evolution. However, the mechanisms governing this resilience remain incompletely understood. In this study, we identified Receptor interacting protein kinase 1 (RIPK1) in hepatocytes as a critical regulator in preserving hepatic homeostasis during metabolic challenges, such as short-term fasting or high-fat dieting. Our results demonstrated that hepatocyte-specific deficiency of RIPK1 sensitized the liver to short-term fasting-induced liver injury and hepatocyte apoptosis in both male and female mice. Despite being a common physiological stressor that typically does not induce liver inflammation, short-term fasting triggered hepatic inflammation and compensatory proliferation in hepatocyte-specific RIPK1-deficient (Ripk1-hepKO) mice. Transcriptomic analysis revealed that short-term fasting oriented the hepatic microenvironment into an inflammatory state in Ripk1-hepKO mice, with up-regulated expression of inflammation and immune cell recruitment-associated genes. Single-cell RNA sequencing further confirmed the altered cellular composition in the liver of Ripk1-hepKO mice during fasting, highlighting the increased recruitment of macrophages to the liver. Mechanically, our results indicated that ER stress was involved in fasting-induced liver injury in Ripk1-hepKO mice. Overall, our findings revealed the role of RIPK1 in maintaining liver homeostasis during metabolic fluctuations and shed light on the intricate interplay between cell death, inflammation, and metabolism.

Receptor Interacting Serine/Threonine Kinase 1 (RIPK1) is widely expressed and integral to inflammatory and cell death responses. Autosomal recessive RIPK1-deficiency, due to biallelic loss of function mutations in RIPK1, is a rare inborn error of immunity (IEI) resulting in uncontrolled necroptosis, apoptosis and inflammation. Although hematopoietic stem cell transplantation (HSCT) has been suggested as a potential curative therapy, the extent to which disease may be driven by extra-hematopoietic effects of RIPK1-deficiency, which are non-amenable to HSCT, is not clear. We present a multi-centre, international review of an additional 5 RIPK1-deficient children who underwent HSCT. All patients presented with very early onset inflammatory bowel disease, 2 also suffered from inflammatory arthritis. Median age at transplant was 3 years (range 1-5 years); 1 received matched sibling marrow, 1 matched unrelated peripheral blood stem cells (PBSC), 2 TCRαβ/CD19-depleted PBSC from maternal-haploidentical donors, and 1 had TCRαβ/CD19-depleted PBSC from a mismatched unrelated donor. All received reduced-toxicity conditioning, based on treosulfan (n = 4) or busulfan (n = 1); 1 patient underwent a successful second transplant following autologous reconstitution. Four of five patients (80%) survived; 1 child died due to multi-drug resistant pseudomonas infection and multi-organ failure. With a median duration of 14 months follow-up, 2 survivors were disease-free, and 2 had substantially improving enteropathy. These findings demonstrated that HSCT is a potential curative therapy for RIPK1-deficiency.

Urinary tract infections are among the most frequently occurring forms of infection, and inflammation and tissue damage contribute significantly to symptoms, e.g., dysuria and urge. Canephron N is an orally bioavailable herbal medicine with anti-inflammatory, spasmolytic, anti-adhesive, and anti-nociceptive therapeutic effects that is approved for the treatment of uncomplicated urinary tract infections. Here, we used renal tubular epithelial HK-2 cells to study the anti-inflammatory and cytoprotective effects and molecular mechanisms of its active component, BNO 2103. BNO 2103 suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation by lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα) and prevented inhibitory κB kinase (IKK)-dependent phosphorylation and degradation of inhibitor of nuclear factor kappa B alpha (IκBα). BNO 2103 also suppressed the inflammation-specific S536 phosphorylation of the NF-κB subunit p65 and the production of a specific set of inflammatory cytokines. Unlike other NF-κB inhibitors, BNO 2103 demonstrated cytoprotection against TNFα-induced cytotoxicity. Our data suggest that BNO 2103 acts primarily through the mitogen-activated protein kinase p38 (p38 MAPK)-MAPK-activated protein kinase 2 (MK2) axis by promoting receptor-interacting serine/threonine protein kinase 1 (RIPK1) phosphorylation at S320. Simultaneously, it suppresses S166 autophosphorylation and subsequent activation of RIPK1, which is required for apoptotic and necroptotic responses to TNFα. This study confirms Canephron N as an effective alternative to traditional anti-inflammatory drugs and provides initial evidence of its ability to inhibit apoptosis and necroptosis in the urogenital system. It also presents a detailed pathway investigation that identifies the specific targets of Canephron N within the NF-κB signaling cascade.

The prevalence of drug-induced liver injury (DILI) and viral liver infections presents significant challenges in modern healthcare and contributes to considerable morbidity and mortality worldwide. Concurrently, metabolic dysfunctionassociated steatotic liver disease (MASLD) has emerged as a major public health concern, reflecting the increasing rates of obesity and leading to more severe complications such as fibrosis and hepatocellular carcinoma. X-box binding protein 1 (XBP1) is a distinct transcription factor with a basic-region leucine zipper structure, whose activity is regulated by alternative splicing in response to disruptions in endoplasmic reticulum (ER) homeostasis and the unfolded protein response (UPR) activation. XBP1 interacts with a key signaling component of the highly conserved UPR and is critical in determining cell fate when responding to ER stress in liver diseases. This review aims to elucidate the emerging roles and molecular mechanisms of XBP1 in liver pathogenesis, focusing on its involvement in DILI, viral liver infections, MASLD, fibrosis/cirrhosis, and liver cancer. Understanding the multifaceted functions of XBP1 in these liver diseases offers insights into potential therapeutic strategies to restore ER homeostasis and mitigate liver damage.

In this study, seventeen isobavachalcone (IBC) derivatives (1-17) were synthesised, and evaluated for their cytotoxic activity against three human lung cancer cell lines. Among these derivatives, compound 16 displayed the most potent cytotoxic activity against H1975 and A549 cells, with IC50 values of 4.35 and 14.21 μM, respectively. Compared with IBC, compound 16 exhibited up to 4.11-fold enhancement of cytotoxic activity on human non-small cell lung cancer H1975 cells. In addition, we found that compound 16 suppressed H1975 cells via inducing apoptosis and necroptosis. The initial mechanism of compound 16 induced cell death in H1975 cells involves the increasing of Bax/Bcl-2 ratio and Cyt C protein level, down-regulating of Akt protein level, and cleaving caspase-9 and -3 induced apoptosis; the up-regulation of RIP3, p-RIP3, MLKL, and p-MLKL levels induced necroptosis. Moreover, compound 16 also caused mitochondrial dysfunction, thereby decreasing cellular ATP levels, and resulting in excessive reactive oxygen species (ROS) accumulation.

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.

Necroptosis is a highly regulated form of necrotic cell death that plays an essential role in pathogen defense and tissue homeostasis. Abnormal regulation of the necroptotic pathway has been implicated in the pathogenesis of various human diseases, including cancer, inflammatory, and neurodegenerative diseases. Receptor-interacting protein kinase 1 (RIPK1) serves as a crucial regulator of the necroptotic signaling pathway and has been identified as a potential therapeutic target. Mechanistically, RIPK1 serves as both a protein kinase and a scaffolding protein, fulfilling its dual function through a combination of kinase activity-dependent and kinase activity-independent mechanisms. Thus, employing a targeted RIPK1 knockdown strategy is a highly effective means of inhibiting RIPK1 functions. To achieve a targeted RIPK1 knockdown, we generated a RIPK1-PROTAC, MS2031, by connecting the ZB-R-55 RIPK1 binder to the VHL ligand, thereby recruiting the CUL2-RING-VHL (CRL2VHL) E3 ubiquitin ligase complex for targeted degradation of RIPK1 through the 26S proteasome. Notably, MS2031 treatment effectively reduced the abundance of RIPK1 protein in the nanomolar range in various cell lines we examined, including HT-29 and T47D cells, and modulated the necroptosis signaling pathway. These results suggest that MS2031 may hold potential for the treatment of human diseases resulting from aberrant regulation of RIPK1.

Excessive chondrocyte death is a critical player in the process of osteoarthritis (OA). The present study was aimed to study the role of receptor-interacting serine/threonine kinase (RIP) 1-mediated signaling for programmed cell death in OA.

In the present study, RIP1 protein expression was evaluated in mouse OA cartilage and cultured primary murine chondrocytes exposed to tumor necrosis factor-alpha (TNF-α). Protein expression involved in necroptosis and apoptosis and chondrocyte-derived extracellular matrix were examined. Inhibition of RIP1 was conducted using the RNAi technique and pharmacological inhibition. Western blot, immunohistochemistry, and immunofluorescence examination were applied.

The protein presence of RIP1, but not RIP3, was increased in the mouse OA tissue and cultured chondrocytes exposed to TNF-α. Knockdown of RIP1 increased protein expression of collagen II and sex-determining region Y-box transcription factor 9, and reduced protein expression of matrix metallopeptidases 13 and a disintegrin and metalloproteinase with thrombospondin motifs 5. Inhibition of RIP1 reduced the phosphorylated NF-κB signals, decreased cell apoptosis, and restored extracellular matrix expression in cultured chondrocytes. Both RNAi and pharmacological inhibition of RIP1 decelerated the progress of OA in mice.

RIP1 regulates chondrocyte apoptosis through NF-κB signaling. Inhibition of RIP1 provides a novel therapeutic approach for OA therapy.

TANK-binding kinase 1 (TBK1) is a pivotal mediator of innate immunity, activated by receptors such as mitochondrial antiviral signaling protein (MAVS), stimulator of interferon genes (STING), and TIR-domain-containing adaptor inducing interferon-β (TRIF). It modulates immune responses by exerting influence on the type I interferons (IFN-Is) signaling and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, Over the past few years, TBK1 multifaceted role in both immune and inflammatory responses is increasingly recognized.

This review aims to scrutinize how TBK1 operates within the NF-κB pathway and the interferon regulatory transcription factor 3 (IRF3)-dependent IFN-I pathways, highlighting the kinases and other molecules involved in these processes. This analysis reveals the distinctive characteristics of TBK1's involvement in these pathways. Furthermore, it has been observed that the role of TBK1 in exerting anti-inflammatory or pro-inflammatory effects is contingent upon varying pathological conditions, indicating a multifaceted role in immune regulation.

TBK1's evolving role in various diseases and the potential of TBK1 inhibitors as therapeutic agents are explored. Targeting TBK1 may provide new strategies for treating inflammatory disorders and autoimmune diseases associated with IFN-Is, warranting further investigation.

Mitophagy, the cellular process of selectively eliminating damaged mitochondria, plays a crucial role in maintaining metabolic balance and preventing insulin resistance, both key factors in type 2 diabetes mellitus (T2DM) development. When mitophagy malfunctions in diabetic neuropathy, it triggers a cascade of metabolic disruptions, including reduced energy production, increased oxidative stress, and cell death, ultimately leading to various complications. Thus, targeting mitophagy to enhance the process may have emerged as a promising therapeutic strategy for T2DM and its complications. Notably, plant-derived compounds with β-cell protective and mitophagy-stimulating properties offer potential as novel therapeutic agents. This review highlights the intricate mechanisms linking mitophagy dysfunction to T2DM and its complications, particularly neuropathy, elucidating potential therapeutic interventions for this debilitating disease.

The pyroptosis of cardiomyocytes has become an essential topic in heart failure research. The abnormal accumulation of these biological factors, including angiotensin II, advanced glycation end products, and various growth factors (such as connective tissue growth factor, vascular endothelial growth factor, transforming growth factor beta, among others), activates the nuclear factor-κB (NF-κB) signaling pathway in cardiovascular diseases, ultimately leading to pyroptosis of cardiomyocytes. Therefore, exploring the underlying molecular biological mechanisms is essential for developing novel drugs and therapeutic strategies. However, our current understanding of the precise regulatory mechanism of this complex signaling pathway in cardiomyocyte pyroptosis is still limited. Given this, this study reviews the milestone discoveries in the field of pyroptosis research since 1986, analyzes in detail the similarities, differences, and interactions between pyroptosis and other cell death modes (such as apoptosis, necroptosis, autophagy, and ferroptosis), and explores the deep connection between pyroptosis and heart failure. At the same time, it depicts in detail the complete pathway of the activation, transmission, and eventual cardiomyocyte pyroptosis of the NF-κB signaling pathway in the process of heart failure. In addition, the study also systematically summarizes various therapeutic approaches that can inhibit NF-κB to reduce cardiomyocyte pyroptosis, including drugs, natural compounds, small molecule inhibitors, gene editing, and other cutting-edge technologies, aiming to provide solid scientific support and new research perspectives for the prevention and treatment of heart failure.

Cartilage, a critical tissue for joint function, often degenerates due to osteoarthritis (OA), rheumatoid arthritis (RA), and trauma. Recent research underscores necroptosis, a regulated form of necrosis, as a key player in cartilage degradation. Unlike apoptosis, necroptosis triggers robust inflammatory responses, exacerbating tissue damage. Key mediators such as receptor-interacting serine/threonine-protein kinase-1 (RIPK1), receptor-interacting serine/threonine-protein kinase-3(RIPK3), and mixed lineage kinase domain-like (MLKL) are pivotal in this process. Studies reveal necroptosis contributes significantly to OA and RA pathophysiology, where elevated RIPK3 and associated proteins drive cartilage degradation. Targeting necroptotic pathways shows promise; inhibitors like Necrostatin-1 (Nec-1), GSK'872, and Necrosulfonamide (NSA) reduce necroptotic cell death, offering potential therapeutic avenues. Additionally, autophagy's role in mitigating necroptosis-induced damage highlights the need for comprehensive strategies addressing multiple pathways. Despite these insights, further research is essential to fully understand necroptosis' mechanisms and develop effective treatments. This review synthesizes current knowledge on necroptosis in cartilage degeneration, aiming to inform novel therapeutic approaches for OA, RA, and trauma.

Microglia are primarily involved in inflammatory reactions and oxidative stress in the brain; as such reducing microglial activation has been proposed as a potential therapeutic strategy for neurodegenerative disorders. Herein, we investigated the anti-inflammatory and antioxidant activities of coniferaldehyde (CFA), a naturally occurring cinnamaldehyde derivative, on activated microglia to evaluate its therapeutic potential. CFA inhibited the production of nitric oxide (NO) and proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. CFA also inhibited intracellular reactive oxygen species levels and oxidative stress markers such as 4-HNE and 8-OHdG. Detailed mechanistic studies showed that CFA exerted anti-inflammatory effects by inhibiting TAK1-mediated MAP kinase/NF-κB activation and upregulating AMPK signaling pathways. In addition, CFA exerted antioxidant effects by inhibiting the NADPH oxidase subunits and by increasing the expression of antioxidant enzymes such as HO-1, NQO1, and catalase by upregulating Nrf2 signaling. Finally, we confirmed the effects of CFA on the brains of the LPS-injected mice. CFA inhibited microglial activation and the expression of proinflammatory markers and increased Nrf2-driven antioxidant enzymes. Furthermore, CFA inhibited the production of 4-HNE and 8-OHdG in the brains of LPS-injected mice. As a result, CFA's significant anti-inflammatory and antioxidant properties may have therapeutic applications in neuroinflammatory disorders related with oxidative stress and microglial activation.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) shows promising therapeutic potential in cancer treatment as it is able to trigger extrinsic apoptotic pathways by binding to the cognate death receptor, causing broad-spectrum apoptosis in cancer cells with negligible toxicity to normal cells. However, the majority of cancers display resistance to TRAIL, limiting its clinical utility. Overcoming resistance to TRAIL therapies remains a challenge in the development of effective anti-cancer strategies. To address the limitations of TRAIL therapy, a viable alternative approach involves combining TRAIL with more potent drugs compared to monotherapy. This combination strategy aims to induce synergistic effects or sensitize drug-resistant cancer cells. This review provides an overview of relevant modalities of TRAIL combination therapy, highlighting different drug classes. The findings demonstrate that combining TRAIL with other agents can effectively counteract resistance observed with TRAIL therapies in cancer. These findings lay a foundation for future advancements in TRAIL-based therapies for treating various cancers.

Neuroinflammation is an immune response in the central nervous system and poses a significant threat to human health. Studies have shown that the receptor serine/threonine protein kinase family (RIPK) family, a popular research target in inflammation, has been shown to play an essential role in neuroinflammation. It is significant to note that the previous reviews have only examined the link between RIPK1 and neuroinflammation. However, it has yet to systematically analyze the relationship between the RIPK family and neuroinflammation. Activation of RIPK1 promotes neuroinflammation. RIPK1 and RIPK3 are responsible for the control of cell death, including apoptosis, necrosis, and inflammation. RIPK1 and RIPK3 regulate inflammatory responses through the release of damage in necroptosis. RIPK1 and RIPK3 regulate inflammatory responses by releasing damage-associated molecular patterns (DAMPs) during necrosis. In addition, activated RIPK1 nuclear translocation and its interaction with the BAF complex leads to upregulation of chromatin modification and inflammatory gene expression, thereby triggering inflammation. Although RIPK2 is not directly involved in regulating cell death, it is considered an essential target for treating neurological inflammation. When the peptidoglycan receptor detects peptidoglycan IE-DAP or MDP in bacteria, it prompts NOD1 and NOD2 to recruit RIPK2 and activate the XIAP E3 ligase. This leads to the K63 ubiquitination of RIPK2. This is followed by LUBAC-mediated linear ubiquitination, which activates NF-KB and MAPK pathways to produce cytokines and chemokines. In conclusion, there are seven known members of the RIPK family, but RIPK4, RIPK5, RIPK6, and RIPK7 have not been linked to neuroinflammation. This article seeks to explore the potential of RIPK1, RIPK2, and RIPK3 kinases as therapeutic interventions for neuroinflammation, which is associated with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), ischemic stroke, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI).

Autoimmunity is a normal physiological state that requires immunological homeostasis and surveillance, whereas necroptosis is a type of inflammatory cell death. When necroptosis occurs, various immune system cells must perform their appropriate duties to preserve immunological homeostasis, whether the consequence is expanding or limiting the inflammatory response and the pathological condition is cleared or progresses to the autoimmune disease stage. This article discusses necroptosis based on RIP homotypic interaction motif (RHIM) interaction under various physiological and pathological situations, with the RIPK1-RIPK3-MLKL necrosome serving as the regulatory core. In addition, the cell biology of necroptosis involved in autoimmunity and its application in autoimmune diseases were also reviewed.

Respiratory diseases are a growing concern in public health because of their potential to endanger the global community. Cell death contributes critically to the pathophysiology of respiratory diseases. Recent evidence indicates that necroptosis, a unique form of programmed cell death (PCD), plays a vital role in the molecular mechanisms underlying respiratory diseases, distinguishing it from apoptosis and conventional necrosis. Necroptosis is a type of inflammatory cell death governed by receptor-interacting serine/threonine protein kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like protein (MLKL), resulting in the release of intracellular contents and inflammatory factors capable of initiating an inflammatory response in adjacent tissues. These necroinflammatory conditions can result in significant organ dysfunction and long-lasting tissue damage within the lungs. Despite evidence linking necroptosis to various respiratory diseases, there are currently no specific alternative treatments that target this mechanism. This review provides a comprehensive overview of the most recent advancements in understanding the significance and mechanisms of necroptosis. Specifically, this review emphasizes the intricate association between necroptosis and respiratory diseases, highlighting the potential use of necroptosis as an innovative therapeutic approach for treating these conditions.

Caspase-8-dependent pyroptosis has been shown to mediate host protection from Yersinia infection. For this mode of cell death, the kinase activity of receptor-interacting protein kinase 1 (RIPK1) is required, but the autophosphorylation sites required to drive caspase-8 activation have not been determined. Here, we show that non-canonical autophosphorylation of RIPK1 at threonine 169 (T169) is necessary for caspase-8-mediated pyroptosis. Mice with alanine in the T169 position are highly susceptible to Yersinia dissemination. Mechanistically, the delayed formation of a complex containing RIPK1, ZBP1, Fas-associated protein with death domain (FADD), and caspase-8 abrogates caspase-8 maturation in T169A mice and leads to the eventual activation of RIPK3-dependent necroptosis in vivo; however, this is insufficient to protect the host, suggesting that timely pyroptosis during early response is specifically required to control infection. These results position RIPK1 T169 phosphorylation as a driver of pyroptotic cell death critical for host defense.

Receptor-interacting protein kinase 1 (RIPK1) is a therapeutic target in treating neurodegenerative diseases and cancers. RIPK1 has three distinct functional domains, with the center domain containing a receptor-interacting protein homotypic interaction motif (RHIM), which mediates amyloid formation. The functional amyloid formed by RIPK1 and/or RIPK3 is a crucial intermediate in regulating cell necroptosis. In this study, the amyloid structure of mouse RIPK1, formed by an 82-residue sequence centered at RHIM, is presented. It reveals the "N"-shaped folding of the protein subunit in the fibril with four β-strands. The folding pattern is shared by several amyloid structures formed by proteins with RHIM, with the central β-strand formed by the most conserved tetrad sequence I/VQI/VG. However, the solid-state NMR results indicate a structural difference between mouse RIPK1 and mouse RIPK3. A change in the structural rigidity is also suggested by the observation of weakened signals for mouse RIPK3 upon mixing with RIPK1 to form the RIPK1/RIPK3 complex fibrils. Our results provide vital information to understand the interactions between different proteins with RHIM, which will help us further comprehend the regulation mechanism in cell necroptosis.

Necrosome activation following TLR- or cytokine receptor-signaling results in cell death by necroptosis which is characterized by the rupture of cell membranes and the consequent release of intracellular contents to the extracellular milieu. While necroptosis exacerbates various inflammatory diseases, the mechanisms through which the inflammatory responses are regulated are not clear. We show that the necrosome activation of macrophages results in an upregulation of various pathways, including the mitogen-activated protein kinase (MAPK) cascade, which results in an elevation of the inflammatory response and consequent expression of several cytokines and chemokines. Programming for this upregulation of inflammatory response occurs during the early phase of necrosome activation and proceeds independently of cell death but depends on the activation of the receptor-interacting protein kinase-1 (RipK1). Interestingly, necrosome activation also results in an upregulation of IFNβ, which in turn exerts an inhibitory effect on the maintenance of inflammatory response through the repression of MAPK-signaling and an upregulation of Zfp36. Activation of the interferon-induced gene factor-3 (ISGF3) results in the expression of ZFP36 (TTP), which induces the post-transcriptional degradation of mRNAs of various inflammatory cytokines and chemokines through the recognition of AU-rich elements in their 3'UTR. Furthermore, ZFP-36 inhibits IFNβ-, but not TNFα- induced necroptosis. Overall, these results reveal the molecular mechanism through which IFNβ, a pro-inflammatory cytokine, induces the expression of ZFP-36, which in turn inhibits necroptosis and halts the maintenance of the inflammatory response.

The gut microbiome is a significant factor in the pathophysiology of ulcerative colitis (UC), prompting investigations into the use of probiotic therapies to counter gastrointestinal inflammation. However, while much attention has been given to the therapeutic potential of microbes at the species and strain level, the discovery and application of their metabolic products may offer more precise and controlled solutions in battling disease. In this work, we examined the therapeutic potential of indole lactic acid (ILA) to alleviate inflammation in a murine model of colitis. A previously constructed ILA-producing Escherichia coli Nissle 1917 strain (EcN aldh) and its isogenic non-ILA producing counterpart (EcN) were studied in a murine model of Dextran Sodium Sulfate (DSS) induced colitis. The colitic animals suffered from severe colitic symptoms, with no differentiation between the groups in body weight loss and disease activity index. However, three days after cessation of DSS treatment the EcN aldh-treated mice showed signs of reduced intestinal inflammation, as manifested by lower concentrations of fecal lipocalin-2. Additionally, expression analysis of the inflamed tissue revealed distinct effects of the EcN aldh strain on proteins associated with intestinal health, such as TFF3, occludin and IL-1β expression. These results show no impact of EcN or EcN aldh on acute DSS-induced colitis, but suggest that in particular EcN aldh may assist recovery from intestinal inflammation.

The discovery of regulatory cell death processes has driven innovation in cardiovascular disease (CVD) therapeutic strategies. Over the past decade, ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has been shown to drive the development of multiple CVDs. This review provides insights into the evolution of the concept of ferroptosis, the similarities and differences with traditional modes of programmed cell death (e.g., apoptosis, autophagy, and necrosis), as well as the core regulatory mechanisms of ferroptosis (including cystine/glutamate transporter blockade, imbalance of iron metabolism, and lipid peroxidation). In addition, it provides not only a detailed review of the role of ferroptosis and its therapeutic potential in widely studied CVDs such as coronary atherosclerotic heart disease, myocardial infarction, myocardial ischemia/reperfusion injury, heart failure, cardiomyopathy, and aortic aneurysm but also an overview of the phenomenon and therapeutic perspectives of ferroptosis in lesser-addressed CVDs such as cardiac valvulopathy, pulmonary hypertension, and sickle cell disease. This article aims to integrate this knowledge to provide a comprehensive view of ferroptosis in a wide range of CVDs and to drive innovation and progress in therapeutic strategies in this field.

Necrostatin-1, a small molecular alkaloid, was identified as an inhibitor of necroptosis in 2005. Investigating the fundamental mechanism of Necrostatin-1 and its role in various diseases is of great significance for scientific and clinical research. Accumulating evidence suggests that Necrostatin-1 plays a crucial role in numerous neurological disorders. This review aims to provide a comprehensive overview of the potential functions of Necrostatin-1 in various neurological disorders, offering valuable insights for future research.

Systemic lupus erythematosus (SLE) is a type of autoimmune disease that involves multiple organs involved as well as cytokine dysregulation. The treatment of SLE is still challenging due to the side effects of the different drugs used. Receptor-interacting protein kinase 1 (RIPK1) is a kinase involved in T cell homeostasis and autoinflammation. Although clinical trials have shown that RIPK1 inhibition exhibits significant efficacy in different autoimmune diseases, its role in SLE remains unclear.

MRL/lpr lupus-prone mice received RIPK1 inhibitor ZJU37 or vehicle intraperitoneally for 10 weeks. A BM12-induced chronic graft-versus-host-disease (cGVHD) lupus-like model was introduced in RIPK1 D138N mice or C57BL/6 mice. Nephritis, serum autoantibody levels, dysregulation of adaptive immune response and cytokines were compared in treated and untreated mice.

ZJU37 alleviated the clinical features of the MRL/lpr mice including nephritis and anti-dsDNA antibody production. In addition, ZJU37 treatment reduced the proportion of double-negative T cells in the spleen and the cytokines of TNFα, IFN-γ, IL-6, IL-17 and IL-1β in the serum. Moreover, RIPK1 D138N mice were able to prevent the cGVHD lupus-like model from SLE attack, manifesting as anti-dsDNA antibody production, the proliferation of germinal centre B cells, plasma cells, and T follicular helper cells as well as IgG and C3 deposits in kidneys.

RIPK1 inhibition has a protective effect in the mouse model of SLE and can potentially become a new therapeutic target for SLE in humans.

Necroptosis is a novel form of cell death which is activated when apoptotic cell death signals are disrupted. Accumulating body of observations suggests that noncoding RNAs, which are the lately discovered mystery of the human genome, are significantly associated with necroptotic signaling circuitry. The fate and function of miRNAs have been well documented in human disease, especially cancer. Recently, lncRNAs have gained much attention due to their diverse regulatory functions. Although available studies are currently based on bioinformatic analysis, predicted interactions desires further attention, as these hold significant promise and should not be overlooked. In the light of these, here we comprehensively review and discuss noncoding RNA molecules that play significant roles during execution of necroptotic cell death.

Fibrosis results from excessive scar formation after tissue injury. Injured cells release alarmins such as interleukin 1 (IL-1) α and β as primary mediators initiating tissue repair. However, how alarmins from different cell types differentially regulate fibrosis remains to be explored.

Here, we used tissue specific knockout strategy to illustrate a unique contribution of endothelial cell-derived IL-1α to lung and liver fibrosis. The two fibrotic animal model triggered by bleomycin and CCl4 were used to study the effects of endothelial paracrine/angiocrine IL-1α in fibrotic progression. Human umbilical vein endothelial cells (HUVEC) were performed to explore the production of angiocrine IL-1α at both transcriptional and post-transcriptional levels in vitro.

We found that endothelial paracrine/angiocrine IL-1α primarily promotes lung and liver fibrosis during the early phase of organ repair. By contrast, myeloid cell-specific ablation of IL-1α in mice resulted in little influence on fibrosis, suggesting the specific pro-fibrotic role of IL-1α from endothelial cell but not macrophage. In vitro study revealed a coordinated regulation of IL-1α production in human primary endothelial cells at both transcriptional and post-transcriptional levels. Specifically, the transcription of IL-1α is regulated by RIPK1, and after caspase-8 (CASP8) cleaves the precursor form of IL-1α, its secretion is triggered by ion channel Pannexin 1 upon CASP8 cleavage.

Endothelial cell-produced IL-1α plays a unique role in promoting organ fibrosis. Furthermore, the release of this angiocrine alarmin relies on a unique molecular mechanism involving RIPK1, CASP8, and ion channel Pannexin 1.

RIPK1 inhibitors have emerged as promising candidates for treating diverse diseases, including inflammatory diseases, autoimmune disorders, Alzheimer's disease, and cancer. However, the previously reported binding assays have limited sensitivity and stability, impeding high-throughput screening and robust characterization of the RIPK1 inhibitors. To address this challenge, we introduced two probes, T2-BDP-FL and T3-BDP-FL, derived from distinct RIPK1 inhibitors with different binding modes to establish time-resolved fluorescence resonance energy transfer (TR-FRET) displacement assays. Employing our TR-FRET displacement assays, we quantified the biochemical binding affinities of a series of RIPK1 inhibitors with diverse structural and binding modes for human RIPK1. Consistent results were obtained with these two probes in the TR-FRET displacement assay. Furthermore, we developed a RIPK1 fluorescent probe, T2-BDP589, for the NanoBRET assay. This assay enabled the characterization of RIPK1 target engagement by various RIPK1 inhibitors for both human and mouse RIPK1 in live cells. Our developed fluorescent probe displacement assays offer a sensitive and high-throughput approach to identify RIPK1 inhibitors based on both biochemical and cellular activities.

Hypoxic-ischaemic encephalopathy (HIE) in termed infants remains a significant cause of morbidity and mortality worldwide despite the introduction of therapeutic hypothermia. Depending on the cell type, cellular context, metabolic predisposition and insult severity, cell death in the injured immature brain can be highly heterogenous. A continuum of cell death exists in the H/I-injured immature brain. Aside from apoptosis, emerging evidence supports the pathological activation of necroptosis, pyroptosis and ferroptosis as alternative regulated cell death (RCD) in HIE to trigger neuroinflammation and metabolic disturbances in addition to cell loss. Upregulation of autophagy and mitophagy in HIE represents an intrinsic neuroprotective strategy. Molecular crosstalk between RCD pathways implies one RCD mechanism may compensate for the loss of function of another. Moreover, mitochondrion was identified as the signalling "hub" where different RCD pathways converge. The highly-orchestrated nature of RCD makes them promising therapeutic targets. Better understanding of RCD mechanisms and crosstalk between RCD subtypes likely shed light on novel therapy development for HIE. The identification of a potential RCD converging node may open up the opportunity for simultaneous and synergistic inhibition of cell death in the immature brain.

Innate immunity is not only the first line of host defense against microbial infections but is also crucial for the host responses against a variety of noxious stimuli. Z-DNA binding protein 1 (ZBP1) is a cytosolic nucleic acid sensor that can induce inflammatory cell death in both immune and nonimmune cells upon sensing of incursive virus-derived Z-form nucleic acids and self-nucleic acids via its Zα domain. Mechanistically, aberrantly expressed or activated ZBP1 induced by pathogens or noxious stimuli enables recruitment of TANK binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 to drive type I interferon (IFN-I) responses and activation of nuclear factor kappa B (NF-κB) signaling. Meanwhile, ZBP1 promotes the assembly of ZBP1- and absent in melanoma 2 (AIM2)-PANoptosome, which ultimately triggers PANoptosis through caspase 3-mediated apoptosis, mixed lineage kinase domain like pseudokinase (MLKL)-mediated necroptosis, and gasdermin D (GSDMD)-mediated pyroptosis. In response to damaged mitochondrial DNA, ZBP1 can interact with cyclic GMP-AMP synthase to augment IFN-I responses but inhibits toll like receptor 9-mediated inflammatory responses. This review summarizes the structure and expression pattern of ZBP1, discusses its roles in human diseases through immune-dependent (e.g., the production of IFN-I and pro-inflammatory cytokines) and -independent (e.g., the activation of cell death) functions, and highlights the attractive prospect of manipulating ZBP1 as a promising therapeutic target in diseases.