Apoptosis最新文献

The recent study by Gao et al. (Apoptosis, 2025. https://doi.org/10.1007/s10495-025-02194-x) proposes a compelling paradigm in which a positive feedback loop between glycolysis and nucleus pulposus cell pyroptosis acts as a central driver of intervertebral disc degeneration. Their work provides a crucial mechanistic link between dysregulated metabolism and inflammatory cell death, building upon long-standing observations of lactic acid accumulation and cellular demise in the degenerative disc. While this refined model represents a significant conceptual advance, our commentary identifies several layers of complexity that must be addressed for therapeutic translation. We argue that the proposed cycle operates within a highly specific pathophysiological context, with key concerns including the model’s applicability across the disc’s spatial heterogeneities, potential pathway redundancy upon therapeutic inhibition, and unresolved upstream instigators of the glycolytic shift. Future research must move beyond in vitro models to focus on spatially resolved mapping in human specimens, combinatorial therapeutic strategies, and elucidating the prime movers—mechanical, age-related, or senescent in origin—that initiate this vicious cycle.

Iron-catalyzed lipid peroxidation, a hallmark of the regulated cell death (RCD) known as ferroptosis, has gained prominence in cancer biology, and its application in anticancer treatments is gaining attention. Triggering ferroptosis may curtail the advancement of tumorigenesis, offer opportunities to boost immunotherapy outcomes, and overcome resistance to established oncological interventions. Nevertheless, the function of ferroptosis in immune modulation has not been systematically addressed, particularly in breast carcinoma. This review explores the molecular basis of ferroptosis and discusses the therapeutic implications, particularly in breast carcinoma. Moreover, the complex interrelationship between ferroptosis and immune modulation has been examined, spotlighting how ferroptotic tumor cells can impact simultaneous tumor-suppressive and tumor-promoting immune activities in the breast cancer microenvironment. Furthermore, the involvement of immune cells in regulating ferroptosis has been explored, highlighting the dual interaction dynamics between ferroptosis and immune functions. Additionally, the exploration includes the application of ferroptosis in breast carcinoma immunotherapy, proposing a promising avenue to boost therapeutic efficacy. Ultimately, grasping the bifunctional nature of ferroptosis in immune modulation unveils new perspectives for pioneering breast carcinoma therapies.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease marked by irreversible deposition of the extracellular matrix (ECM) and subsequent disruption of pulmonary architecture. Although current pharmacological interventions, such as Pirfenidone and Nintedanib, are available, they merely decelerate the progression of the disease. Notably, the monocyte count in peripheral blood is strongly correlated with the prognosis and mortality associated with IPF. An elevated monocyte count is observable in the early stages of IPF, with monocyte accumulation in lung tissue persisting throughout the disease's progression. Monocytes are recruited to the lung tissue in response to chemoattractant signals, where they differentiate into macrophages, dendritic cells, and fibrocytes. These differentiated cells are integral to the pathology of IPF, with macrophages, in particular, being identified as pivotal contributors to disease progression. This review aims to elucidate the primary pathways involved in monocyte recruitment to the lungs during IPF and to investigate the crucial roles that monocytes play in the disease's pathogenesis. This review aims to establish a foundation for novel therapeutic strategies targeting monocytes, thereby facilitating early detection and intervention in IPF.

Atherosclerosis (AS), a chronic inflammatory disease characterized by pathological cell death, remains a major cause of cardiovascular morbidity and mortality worldwide. PANoptosis, a recently defined form of inflammatory programmed cell death that integrates pyroptosis, apoptosis, and necroptosis, has attracted increasing attention. Transcriptomic analyses have revealed the upregulation of PANoptosis-related genes in atherosclerotic plaques, suggesting a potential role in disease progression. However, the precise molecular mechanisms through which PANoptosis contributes to AS remain largely undefined. In this review, we comprehensively explore the hypothetical upstream triggers and signaling pathways that may induce PANoptosis in vascular cells under pro-atherogenic conditions, such as dysregulated mitochondrial dynamics, mitochondrial oxidative stress and disturbed shear stress. We also discuss candidate PANoptosomes potentially involved in atherosclerotic contexts, such as ZBP1-, AIM2-, and RIPK1-dependent complexes. Although no selective inhibitors of PANoptosis have been developed, we summarize pharmacological agents targeting core components of the PANoptotic pathway and evaluate their potential implications in therapeutic strategies for AS.

Cancer treatment remains in need of novel therapeutic strategies to improve patient outcomes. Cuproptosis, a recently identified form of immunogenic cell death, is recognized for its significant anticancer potential. However, most cuproptosis-based strategies are still in the preclinical stage, and the limited clinical trials conducted thus far have yielded unsatisfactory results. Cancer cells develop resistance to cuproptosis through mechanisms such as metabolic reprogramming or altered signaling pathways. Investigating how to overcome this resistance is therefore crucial for advancing cuproptosis-based therapies. This review summarizes cellular copper homeostasis and its regulation, compares cuproptosis with other immunogenic cell death modalities, and discusses the factors governing cuproptosis sensitivity. From a translational perspective, this review highlights emerging nanomedicine strategies to enhance cuproptosis sensitivity through metabolic vulnerability targeting and pharmacological reversal of resistance mechanisms. Finally, this review envisions the broader therapeutic potential of cuproptosis modulation beyond oncology. These advances may ultimately redefine clinical paradigms, offering hope for meaningful survival extensions and improved quality of life for cancer patients.

Hepatic fibrosis (HF) is a key pathological process in chronic liver disease progression, driven by hepatic stellate cell (HSC) activation. Quiescent HSCs store vitamin A and maintain extracellular matrix homeostasis. Upon liver injury, HSCs transform into proliferative myofibroblasts, causing collagen deposition and tissue remodeling. This study investigates vitamin A’s role in HSC activation regulation through clinical and animal models linking vitamin A deficiency to HF severity, and mechanistic insights into how all-trans retinoic acid (ATRA) reverses HSC activation via ferroptosis and endoplasmic reticulum stress (ERS). Serum vitamin A levels were compared between 37 healthy controls and 43 chronic liver disease patients. 48 Balb/c mice fed standard or vitamin A-deficient diets for 4 weeks, followed by CCl4-induced HF. Liver function, histopathology (HE/Masson staining), and lipid metabolomics were analyzed. Mice received ATRA either concurrently with CCl4 (early) or post-fibrosis (late). HSC-T6/LX-2 cells were pretreated to induce quiescence, then activated with ferric ammonium citrate (FAC) and ATRA/ERS inhibitors. Mitochondrial function, lipid droplets, and ferroptosis markers were assessed. Clinical data showed significantly lower vitamin A in patients versus controls (p < 0.0001).Vitamin A-deficient mice exhibited worse liver injury (p < 0.05), collagen deposition, and iron accumulation under CCl4. Early ATRA intervention reduced fibrosis and ERS, while late intervention had marginal effects. ATRA suppressed mitochondrial hyperactivity and ERS in HSCs, promoting quiescence via ferroptosis induction. Both clinical and animal experiments consistently demonstrate that vitamin A deficiency is not merely a concomitant phenomenon of liver injury, but rather a key pathogenic factor that drives the vicious cycle of fibrosis by disrupting lipid/iron metabolic homeostasis and exacerbating oxidative stress. During the early fibrotic stage, while iron accumulates in the liver, ERS exerts cytoprotective effects, preventing ferroptosis occurrence. ATRA can inhibit ERS to activate the ferroptosis pathway, thereby reprogramming HSCs toward a quiescent phenotype. This process involves restoration of mitochondrial membrane potential and normal mitochondrial morphology, ultimately reducing fibrogenic substance production.

Introduction

Intervertebral disc degeneration (IVDD) is a predominant cause of low back pain, and mesenchymal stem cell (MSC) transplantation represents a promising therapeutic strategy. However, its efficacy is severely limited by the harsh oxidative microenvironment of the degenerative disc, which rapidly triggers ferroptosis, an iron-dependent form of cell death, in transplanted MSCs.

Method

This review critically appraised current ferroptosis-inhibition strategies, highlighting their transient or single-axis limitations. We then synthesized a hierarchical framework for engineering robust MSC resistance, progressing from dual-target gene circuits and genetic-pharmacological alliances to smart, protective biomaterial niches.

Result

Conventional approaches provide only partial protection. In contrast, advanced multi-layered strategies, including dual-target gene circuits (e.g., the Prominin-2/FBXO22/BACH1 axis) potentiated by genetic-pharmacological alliances (e.g., with TBE56), confer superior, cell-intrinsic resilience, increasing MSC survival by approximately 1.5-fold and significantly improving regenerative outcomes in IVDD models. Furthermore, encapsulating engineered MSCs in responsive biomaterials establishes a protective niche, ensuring sustained function.

Conclusion

The paradigm is shifting from passive protection to active cellular empowerment. Engineering MSCs with multi-layered, comprehensive ferroptosis shielding is fundamental to unlocking their full therapeutic potential. This engineered cellular empowerment strategy represents a paradigm shift from palliative care to potentially curative, regenerative treatment for IVDD, with the potential to fundamentally change clinical management by addressing the root cause of MSC therapy failure.

Programmed cell death in animal species of the order Carnivora is suspected to be unique due to the potential defects in activating the lytic cell death pathways, necroptosis and pyroptosis. In a wide range of species of the order Carnivora, including domestic cats and dogs, racoons, red foxes, and ferrets, the absence of the necroptosis executioner protein MLKL (mixed-lineage kinase domain-like pseudokinase) is suspected to prohibit necroptotic lysis. It remains unclear what type(s) of cell death are activated in canine cells downstream of RIPK3 (receptor-interacting protein kinase 3). Here, we show that activation of RIPK3 by expressing it with a trimerization domain drives PANoptosis in human fibroblasts but activates apoptosis in canine epithelial cells. Expression of trimerizable canine and human RIPK3 in canine cells activated apoptotic cell death dependent on caspases, FAS-associated death domain protein (FADD), and RIPK1. Human RIPK3 in canine cells activated a rapid apoptosis compared to the canine version. Unlike canonical caspase 8 driven apoptosis, RIPK3-driven canine cell apoptosis is associated with the secretion of danger-associated molecular patterns (DAMPs) and pro-inflammatory cytokines. This is the first study defining the function of canine RIPK3 and potentially immunostimulatory, non-lytic, cell death in canine cells. This form of cell death can be further developed to ignite immunity against virus infections and cancer.

Hepatocellular carcinoma (HCC), the third leading cause of cancer-related mortality worldwide, is characterized by a rising incidence and an alarmingly low rate of early diagnosis, presenting a significant global public health challenge. The development of safe and effective therapeutic agents for HCC is therefore a pressing necessity. Sophoraflavanone G (SFG), a bioactive flavonoid derived from Sophora flavescens Ait., has exhibited potent antitumor activity. However, its specific efficacy against HCC and the underlying molecular mechanisms remain poorly elucidated. In vitro studies have demonstrated that SFG suppresses HCC cell proliferation and migration in a dose-dependent manner, induces mitochondrial dysfunction, and activates intrinsic apoptotic pathways. Consistent with these results, in vivo experiments utilizing a HepG2 xenograft model confirmed that SFG, administered at doses ranging from 12.5 to 50 mg/kg, effectively inhibits tumor growth without causing observable toxicity. These findings further support the activation of mitochondrial-dependent apoptosis in response to SFG treatment. Importantly, SFG was also found to interfere with the unidirectional mitochondrial transfer mediated by tunneling nanotubes (TNTs) between cancer-associated fibroblasts (CAFs) and HCC cells. This disruption attenuated the pro-survival influence of the tumor microenvironment and enhanced apoptosis in HCC cells. In summary, this study provides the first evidence that SFG exerts potent anti-HCC effects through dual mechanisms: direct induction of mitochondrial apoptosis and indirect disruption of TNT-mediated stromal support. These findings highlight the therapeutic potential of SFG as a promising candidate for the treatment of HCC.

Graphical abstract

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic contact points between the endoplasmic reticulum (ER) and mitochondria, governing essential cellular processes such as calcium (Ca²⁺) signaling, lipid metabolism, mitochondrial dynamics, and apoptosis. The effective movement of Ca²⁺ from the ER to mitochondria at MAMs is crucial for sustaining bioenergetics and controlling cell fate outcomes like survival or programmed cell death. Recent findings highlight the importance of MAMs in maintaining cellular balance and demonstrate their functional versatility in both healthy and diseased states. Disruption of MAM integrity and signaling is increasingly linked to the development of various diseases, including cancer. In cancer, MAMs demonstrate two regulatory roles— either promoting oncogenic functions or enhancing tumor-suppressive actions based on the molecular context and cellular environment. Changes in the structural framework of MAMs, such as variations in protein makeup and tethering distance between the ER and mitochondria, have been directly linked to several characteristics of tumor formation. Therefore, a deeper understanding of the molecular components and regulatory mechanisms governing MAM function may offer a promising avenue for the development of novel therapeutic strategies aimed at restoring proper organelle communication and counteracting cancer development and progression.