Apoptosis最新文献

Sepsis is a life-threatening condition characterized by high mortality and multi-organ dysfunction. Phoenixin-14 (PNX-14) is an endogenous neuropeptide initially identified in the hypothalamus and is known for its anti-inflammatory, antioxidant, and neuroprotective properties. This study evaluated the protective effects of PNX-14 and dexamethasone (Dexa) against inflammation, oxidative stress, and apoptosis in kidney tissue using a lipopolysaccharide (LPS)-induced sepsis model. Thirty-two male Sprague–Dawley rats were divided into four groups (n = 8): Control (saline), LPS (5 mg/kg, single dose), LPS + PNX-14 (50 μg/kg, twice), and LPS + Dexa (2.5 mg/kg, twice). Kidney tissues were collected eight hours post-LPS administration. Biochemical parameters including creatinine, blood urea nitrogen (BUN), urea, and C-reactive protein (CRP) were measured. Apoptotic markers Bax, Bcl-2, and caspase-3 were assessed immunohistochemically, and apoptosis was detected via TUNEL assay. Inflammatory cytokines interleukin-6 (IL-6) and interleukin-10 (IL-10), along with oxidative stress markers superoxide dismutase (SOD), malondialdehyde (MDA), and myeloperoxidase (MPO), were analyzed by ELISA. LPS significantly increased creatinine, BUN, urea, CRP, Bax, caspase-3, IL-6, IL-10, MDA, MPO, and TUNEL-positive cells, while decreasing Bcl-2 and SOD levels (p < 0.05). Both PNX-14 and Dexa treatments significantly reversed these changes (p < 0.05), reducing inflammation, oxidative stress, and apoptosis. Histological analysis showed marked improvement with Dexa and moderate improvement with PNX-14. The Bax/Bcl-2 ratio was also significantly reduced in treatment groups (p < 0.05). The Bax/Bcl-2 ratio was also significantly reduced in treatment groups (p < 0.05). To the best of our knowledge, this is the first study to demonstrate that PNX-14 exerts renoprotective effects comparable to Dexa in LPS-induced sepsis by modulating inflammatory, oxidative, and apoptotic pathways, suggesting its potential as a therapeutic agent for sepsis-related renal injury.

Colorectal cancer (CRC), a highly prevalent malignant neoplasm worldwide, poses significant challenges in clinical management due to resistance to radiotherapy and chemotherapy. Notably, chemoresistance in CRC is frequently linked to elevated autophagy levels, prompting extensive exploration of combination therapies that integrate chemotherapeutic agents with autophagy modulators, including both inducers and inhibitors. Moreover, the induction of programmed cell death (PCD) in tumor cells has the potential to improve the therapeutic efficacy of anti-tumor treatments and address key challenges related to drug resistance. Pyroptosis and ferroptosis, two distinct types of PCD, have emerged as potential tumor-suppressive mechanisms owing to their unique molecular characteristics. Increasing evidence supports functional crosstalk between these two processes. Autophagy exerts complex regulatory effects on pyroptosis and ferroptosis through multiple functional subtypes. Growing evidence indicates that various pharmacological agents, small molecules, nanocarrier-based delivery systems, and specific autophagic pathways can selectively induce pyroptosis or ferroptosis. Moreover, combining autophagy modulators with standard radiotherapeutic or chemotherapeutic regimens holds significant promise for enhancing treatment outcomes and restore drug sensitivity in CRC. This review systematically summarizes the molecular mechanisms underlying pyroptosis and ferroptosis along with their roles in CRC pathogenesis, elucidates the central regulatory function of autophagy, discusses innovative strategies leveraging autophagy-mediated activation of pyroptosis and ferroptosis, and evaluates the synergistic potential inherent of integrating autophagy modulation with established treatment modalities. Finally, current challenges pertaining to mechanistic research and clinical translation are critically assessed to provide a robust theoretical foundation for future advances in CRC therapeutics.

Triple-negative breast cancer (TNBC) is a clinically aggressive subtype with limited therapeutic strategies. Although long non-coding RNAs (lncRNAs) are increasingly linked to tumor progression, their regulatory role in macrophage polarization during TNBC remains unclear. This study investigates the molecular interplay between lncRNA PVT1 and PPARγ in driving macrophage reprogramming during TNBC progression. Utilizing an orthotopic TNBC mouse model, single-cell RNA sequencing (scRNA-seq) identified nine distinct cell types, with pseudotime trajectory analysis revealing macrophage accumulation in advanced tumor stages. Reannotation of macrophages highlighted M2-like polarization dominance during TNBC development. Bulk sequencing of TNBC macrophages and integrated GEO/TCGA analyses identified PPARγ as a key regulator and PVT1 as a differentially expressed lncRNA in TNBC versus normal tissues. In vitro experiments with THP-1/U937 macrophages demonstrated that PVT1 knockdown or PPARγ modulation altered macrophage polarization, subsequently affecting MDA-MB-231 and MCF-7 breast cancer cell proliferation and invasion. Mechanistically, RNA/DNA pulldown and luciferase assays confirmed that PVT1 recruits NOP56 and E2F1 to form a transcriptional complex, enhancing E2F1-driven PPARγ expression. In vivo, orthotopic tumors generated from PVT1-silenced THP-1/MDA-MB-231 cell mixtures exhibited suppressed growth, increased M1-like macrophages, and elevated apoptosis (TUNEL assay), whereas PPARγ overexpression accelerated tumor progression with M2-dominant infiltration (flow cytometry). These findings establish lncRNA PVT1 as a critical epigenetic scaffold coordinating NOP56-E2F1-PPARγ signaling to polarize macrophages toward a pro-tumorigenic M2 phenotype, thereby fueling TNBC aggressiveness. This study unveils novel therapeutic targets for TNBC by disrupting the PVT1-PPARγ axis to rebalance macrophage dynamics and induce tumor-suppressive immunity.

Environmental pollutants such as heavy metals, pesticides, air pollutants, and industrial chemicals pose serious threats to human health, in part by disrupting mitochondrial function. Mitophagy, a selective autophagic process that eliminates impaired mitochondria, is essential for maintaining mitochondrial and cellular homeostasis. Recent studies have shown that various pollutants can impair or dysregulate mitophagy, particularly through pathways such as PTEN-induced kinase 1 (PINK1)/Parkin-mediated mechanisms, leading to mitochondrial dysfunction, oxidative stress, inflammation, and ultimately contributing to diseases including neurodegeneration, cancer, and metabolic disorders. This review comprehensively summarizes the mechanisms by which different classes of environmental pollutants regulate mitophagy, the molecular signaling pathways involved, and the downstream effects on cellular health. Furthermore, this review also discusses current drugs and natural interventions that can alleviate pollutant-induced mitophagy dysfunction, such as melatonin, resveratrol, selenium, and stem cell therapy. By integrating the latest advances in environmental toxicology and mitochondrial biology, the review offers novel perspectives on the role of mitophagy in pollutant toxicity and highlights promising strategies for mitigating the adverse health effects of environmental exposures.

Intervertebral disc degeneration (IDD) is closely linked to nucleus pulposus (NP) cell death exhibiting a PANoptotic phenotype—concurrent activation of apoptosis, necroptosis, and pyroptosis—yet its molecular regulators remain unclear. Here we identify DNA damage-inducible transcript 3 (DDIT3) as a key mediator of inflammatory PANoptosis. RNA sequencing of TNF-α–treated human NP cells revealed robust DDIT3 upregulation, consistent with observations in degenerated human discs and a rat needle-puncture IDD model. In vitro, DDIT3 knockdown (siRNA) reduced PANoptosis markers (NLRP3, caspase-1 p20, Bax, cleaved caspase-3, MLKL, p-MLKL), inflammatory cytokines (IL-1β, IL-18), and reactive oxygen species (ROS), whereas DDIT3 overexpression produced the opposite effects. Mechanistically, transcriptomics and luciferase assays indicated that DDIT3 transactivates CUL3; direct promoter binding was corroborated by chromatin immunoprecipitation and electrophoretic mobility shift assays. Molecular docking (predictive) together with co-immunoprecipitation supported a CUL3–caspase-8 interaction, and CUL3-dependent polyubiquitination enhanced caspase-8 activation. In vivo, lentiviral DDIT3 silencing mitigated disc degeneration in rat puncture models, preserved aggrecan/collagen II, and reduced PANoptotic readouts, whereas DDIT3 overexpression accelerated matrix loss. Collectively, these findings position the DDIT3–CUL3–caspase-8 axis as a central regulator of inflammatory PANoptosis in NP cells and a potential therapeutic target for halting IDD progression.

Melanoma exhibits significant resistance to conventional apoptosis-based therapies, underscoring the need for alternative strategies to induce cancer cell death. Pyroptosis is a pro-inflammatory form of programmed cell death characterized by caspase-1 activation, gasdermin D cleavage, and interleukin-1β (IL-1β) release. In this study, transcriptomic analysis revealed that aripiprazole induces robust inflammatory signaling in melanoma cells. The antipsychotic drug aripiprazole was found to trigger pyroptosis in BRAF-mutant melanoma cells, leading to caspase-1 activation, gasdermin D cleavage, and increased secretion of pro-inflammatory cytokines. Aripiprazole treatment also activated the MAPK signaling cascade and induced G1 cell-cycle arrest. Notably, aripiprazole rapidly upregulated the expression of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an innate immune receptor that acts upstream of inflammasome activation and simultaneously regulates MAPK and NF-κB signaling pathways. Genetic and pharmacological evidence demonstrated that NOD2 is essential for aripiprazole-induced pyroptosis and downstream signal propagation. This study provides mechanistic insight into the anti-cancer potential of aripiprazole and supports the broader investigation of serotonergic drugs as immunomodulatory agents in cancer therapy.

Psoriasis is a common, chronic inflammatory skin disorder with a high prevalence across all age groups, imposing a substantial burden on both individuals and society. It is characterized by epidermal hyperplasia and infiltration of immune cells into the dermis. Within the psoriatic microenvironment, epidermal keratinocytes contribute to a self-amplifying inflammatory response through the generation of “feed-forward” inflammation. Contrary to the earlier view of keratinocytes as passive “victims” in psoriasis pathogenesis, growing evidence supports their role as “active drivers” of disease progression. Programmed cell death (PCD) in keratinocytes interacts dynamically with immune cells, cytokines, damage-associated molecular patterns (DAMPs), and other factors, forming a complex regulatory network. Multiple PCD-related molecules in keratinocytes have been identified, many of which hold promise as biomarkers or therapeutic targets. These molecules may inform the development of new diagnostic and treatment strategies for psoriasis. This review outlines the major PCD pathways in keratinocytes—apoptosis, necroptosis, ferroptosis, and pyroptosis—and examines their roles in psoriasis. We also summarize recent therapeutic advances that modulate keratinocyte cell death and discuss how these pathways shape the cutaneous immune microenvironment.

Osteoarthritis (OA) is a prevalent degenerative joint disease with complex and multifactorial etiology, primarily affecting elderly populations. Factors such as mechanical stress and aging contribute to cartilage degeneration and joint damage. OA manifests through extracellular matrix (ECM) degradation in chondrocytes, decreased chondrocyte viability, and is associated with significant incidence and disability. Recent research indicates that multiple patterns of programmed cell death (PCD), including apoptosis, pyroptosis, necroptosis, autophagy, ferroptosis, cuproptosis, and PANoptosis, regulate the survival and death of chondrocytes through intricate molecular networks, thereby contributing to the onset and progression of OA.This review elucidates the molecular underpinnings of these seven forms of PCD and emphasizes their significance in OA pathology, with a view to providing new perspectives for in-depth research into the pathogenesis of OA and the development of targeted drugs.

Pancreatic cancer (PC) is a lethal malignancy with limited therapeutic options, characterized by tumor suppressor loss and metabolic–stromal crosstalk. This study aimed to introduce nuclear factor I A (NFIA) as a key tumor suppressor whose downregulation in PC was correlated with advanced tumor stages and poor prognosis. Functionally, NFIA overexpression suppressed PC cell proliferation, migration, and invasion, whereas NFIA silencing exacerbated these malignant phenotypes. Mechanistically, NFIA directly repressed the transcription of the glycolytic enzyme PKM, thereby attenuating glucose uptake and lactate production. Lactate generated from NFIA deficiency–induced glycolysis promoted histone lactylation, which epigenetically upregulated fibronectin 1 (FN1) expression in both cancer cells and cancer-associated fibroblasts. Elevated FN1 activated the integrin α5β1–FAK–PI3K–Akt signaling axis, thereby fostering invasive and metastatic behavior. Furthermore, NFIA transcriptionally suppressed FN1 expression, establishing a dual regulatory mechanism that bridged metabolic reprogramming and extracellular matrix remodeling. Collectively, our study indicated NFIA as a key tumor suppressor of PC progression, orchestrating the crosstalk between glycolysis inhibition and FN1–integrin pathway inactivation. These findings position NFIA restoration as a therapeutic strategy to disrupt metabolic–stromal synergy in aggressive PC, offering insights into the epigenetic–metabolic interplay underlying tumor microenvironment evolution.

The core pathological mechanism of diabetes mellitus and its complications is rooted in the interactive regulation between immunometabolic dysregulation and inflammatory programmed cell death, with PANoptosis serving as a critical hub in this process. PANoptosis is a distinct innate immune-mediated inflammatory lytic cell death pathway initiated by pattern-recognition receptors and propagated via the PANoptosome complex, which plays a critical hub role in the interactive regulation between immunometabolic dysregulation and inflammatory programmed cell death in diabetes. Under diabetic conditions, metabolic stressors, including chronic hyperglycemia and lipotoxicity, directly promote PANoptosome assembly by disrupting cellular energy balance, inducing mitochondrial dysfunction, and accumulating reactive oxygen species. Meanwhile, the activation of immune signaling pathways such as TLR/NLR further amplifies the PANoptotic effect, leading to pancreatic β-cell loss, exacerbated adipose tissue inflammation, and vascular endothelial damage, ultimately driving the progression of complications such as nephropathy, retinopathy, and neuropathy. There exists a bidirectional regulation between PANoptosis and immunometabolism: metabolic intermediates such as succinate and lactate can enhance the expression of PANoptosis-related molecules by activating the SUCNR1-NF-κB pathway or regulating histone lactylation; in turn, DAMPs released by PANoptosis, such as HMGB1 and IAPP, reshape the metabolic phenotype of immune cells by activating TLR/RAGE signaling. This review systematically synthesizes the immunometabolic regulatory mechanisms of PANoptosis in diabetes and its complications, clarifies its cell-specific roles in β-cells, immune cells, and vascular tissues, and evaluates therapeutic strategies targeting the metabolic-immune crosstalk axis and core PANoptotic components, providing new theoretical basis and potential targets for precision intervention in diabetes and its complications.