Anthracycline-induced cardiotoxicity (AIC), in which ferroptosis-related cardiomyocyte injury has been implicated, remains a major challenge in oncology. This study investigates the therapeutic potential of an apolipoprotein A1 (ApoA1) mimetic peptide, L-4 F, in epirubicin-induced cardiotoxicity (EIC) in a rat model. Rats received epirubicin (2.5 mg/kg/week, i.p.) for six weeks to establish the EIC model, with or without concurrent ApoA1 mimetic treatment (L-4 F, 1 mg/kg/day). Cardiac function was assessed by echocardiography. Myocardial tissues underwent single-nucleus RNA sequencing (snRNA-seq), RegDiffusion-based gene regulatory network inference, Western blot, immunohistochemistry, and ELISA. Mechanistic studies used H9C2 cardiomyoblasts and CMEC-H9C2 Transwell co-culture systems under EPI exposure, with ApoA1 treatment, endothelial IL-33 knockdown, and Ferrostatin-1 (Fer-1) rescue. Glutathione peroxidase 4 (GPX4) expression, intracellular iron, lipid peroxidation, and cell viability were assessed. ApoA1 treatment alleviated diastolic dysfunction and weight loss and partially improved global longitudinal strain. snRNA-seq revealed substantial transcriptional remodeling in cardiomyocytes. RegDiffusion analysis identified coordinated reprogramming of transcription factor regulons, including Ppara, Fos, Egr1, and Klf4. ApoA1 treatment was associated with an anti-ferroptotic pattern of ferroptosis-related gene expression, with relatively higher Gpx4 and Slc7a11 expression and lower Tfrc expression, consistent with increased GPX4 protein levels. Intercellular communication analysis suggested enhanced IL-33/ST2-mediated endothelial-cardiomyocyte signaling following ApoA1 treatment. In vitro, ApoA1 restored GPX4 expression and reduced iron accumulation under EPI stress; these effects were potentiated in co-culture conditions and attenuated by endothelial IL-33 knockdown. In the rescue model, ApoA1 and Fer-1 partially restored viability and reduced MDA. ApoA1 alone did not significantly lower C11-BODIPY oxidation, whereas the combination gave the most consistent effect. ApoA1 attenuates EIC and is associated with modulation of GPX4-linked ferroptosis-related responses. This protective effect may involve endothelial-cardiomyocyte crosstalk, with endothelial IL-33 signaling acting as a partial contributor. These findings highlight a potential cardioprotective mechanism.
Immune checkpoint inhibitors (ICIs) have reshaped cancer treatment; however, durable clinical benefit remains limited by primary and acquired resistance, frequently associated with T cell dysfunction within an immunosuppressive tumor microenvironment. Beyond their classical role in hemostasis, platelets have emerged as active immune modulators capable of shaping antitumor T cell responses. Accumulating evidence indicates that platelets engage T cells through contact-dependent receptor–ligand interactions, immunomodulatory soluble factors, and the transfer of checkpoint-associated extracellular vesicles, thereby reinforcing dysfunctional T cell states and constraining responses to immune checkpoint blockade. In this review, we synthesize current mechanistic insights into platelet–T cell crosstalk, delineate its differential impact across T cell subsets, and integrate these processes into a broader framework of immune evasion and immunotherapy resistance. We further discuss emerging translational strategies aimed at modulating platelet immune functions, including antiplatelet drug repurposing, selective targeting of platelet–immune interfaces, and metabolic interventions to restore T cell fitness. Collectively, this work reframes platelets as non-canonical immune regulatory nodes and highlights platelet–T cell interactions as a therapeutically actionable layer of immune regulation with implications for improving and personalizing cancer immunotherapy. Platelets act as underappreciated immune regulators that shape T cell function inthe tumor microenvironment Platelet–T cell interactions arise through contact-dependent signaling, solublemediators, and platelet-derived extracellular vesicles Platelet cues can reprogram multiple T cell compartments, with subset- and contextspecificoutcomes This crosstalk may contribute to immune checkpoint inhibitor resistance byreinforcing dysfunctional T cell states Targeting platelet immune functions offers a rationale for combination strategiesalongside immunotherapy
Heart failure (HF) is defined as a condition characterized by abnormalities in the heart's structure or function, which lead to the heart's inability to deliver oxygen to tissues in a timely manner, and it may progress to symptoms such as muscle atrophy of skeletal muscles. Our research primarily focuses on Glycine N-methyltransferase (GNMT), an enzyme that utilizes S-adenosylmethionine (SAM) to catalyze glycine, in order to explore its specific role in HF-induced skeletal muscle atrophy. In this study, an HF rat model induced by abdominal aortic constriction (AAC) and a C2C12 muscle atrophy cell model induced by angiotensin Ⅱ (Ang Ⅱ) were established. Echocardiography, ELISA, and HE staining were used to evaluate the damage of myocardial and gastrocnemius tissues. Immunofluorescence staining was used to assess skeletal muscle atrophy. Western blot, IP, and Co-IP were used to determine the molecular mechanism. In HF rats, the expressions of GNMT and Mitochondrial Fo complex subunit F2 (ATP5J2) were significantly decreased. Overexpression of GNMT/ATP5J2 contributed to alleviate HF-induced skeletal muscle atrophy. GNMT elevated the succinylation level and protein stability of ATP5J2 at lysine 22 (K22) by consuming glycine, and simultaneously reduced its ubiquitination level. Succinylated ATP5J2 improved mitochondrial homeostasis to mitigate HF-induced skeletal muscle atrophy. This study elucidated the function of the GNMT-ATP5J2 axis in HF-induced skeletal muscle atrophy and clarified the underlying molecular mechanism, providing a new theoretical basis for the treatment of HF-induced skeletal muscle atrophy.
Programmed cell death (PCD) has expanded to more than ten diverse lytic modalities such as pyroptosis, necroptosis, ferroptosis, and disulfidptosis. In 2025, Wang et al. reported in Cell a previously unrecognized form of lytic cell death, termed mitoxyperilysis, in which plasma membrane rupture is driven not by canonical pore-forming or membrane-disrupting enzymatic effectors, but by mitochondria-mediated oxidative injury localized to the cell periphery. This process is initiated by the synergistic combination of innate immune activation and metabolic disruption, referred to as IIAMD, which induces mitochondrial oxidative damage and promotes the sustained retention of injured mitochondria at the plasma membrane, a preceding state termed mitoxyperiosis. Mechanistically, mTORC2, particularly through its defining subunit RICTOR, functions as a central regulatory switch that licenses the transition from tolerated oxidative stress to lethal membrane rupture. By suppressing RhoA-dependent actin remodeling and lamellipodia formation, mTORC2 prevents the spatial clearance of damaged mitochondria from the cell cortex, thereby allowing locally concentrated oxidative stress to overwhelm membrane repair and antioxidant defenses. This two-step framework establishes the concept of spatial licensing in oxidative cell death, emphasizing that lethality depends not only on the amount of reactive oxygen species, but also on their subcellular topology. However, mitoxyperilysis has not yet been implicated in any human disease on the basis of direct evidence. In this review, we summarize the emerging mechanisms of mitoxyperilysis, compare it with established lytic death pathways, and discuss its potential relevance to inflammatory disease, sepsis, ischemic injury, and cancer, as well as therapeutic strategies targeting mTORC2, RhoA signaling, and mitochondrial protection.
Immunotherapy has improved outcomes for a subset of patients with locally advanced cervical cancer. However, many tumors remain immunologically “cold” and fail to respond. Strategies that enhance tumor immunogenicity are therefore of increasing interest. Necroptosis, a regulated form of inflammatory cell death, has emerged as a potential mechanism capable of promoting the anti-tumor immune responses through the release of damage-associated molecular patterns and enhanced antigen presentation. In this study, we performed a systematic review and transcriptomic cross-study consensus analysis of all studies carried out describing the role and mechanisms of necroptosis occurrence in cervical cancers. We analyzed all published necroptosis-related prognostic gene signatures and integrated these findings into an exploratory transcriptomic analyses to identify mechanistic insights into interlinked biological pathways, and potential therapeutic targets. Following PRISMA guidelines, we analyzed seven published prognostic models, from studies using RNA sequencing and least absolute shrinkage and selection operator (LASSO)-based feature selection to generate a prognostic risk score for patients. We then conducted a comparative analyses of eight overlapping genes and their reported risk score coefficients. Across studies, seven necroptosis-related genes were identified, many of which are functionally linked to mitochondrial transport and permeability regulation, reactive oxygen species (ROS) generation, and inflammatory signaling. Overall, our findings support a key role for necroptosis in cervical cancer, where activation thereof is generally associated with enhanced immune infiltration and activation; thereby improved prognosis. These findings position necroptosis as a promising target for combination therapy strategies aimed at converting immunologically “cold” tumors into more responsive phenotypes. By integrating published signatures with exploratory analyses, we identify potential avenues to modulate necroptotic signaling in ways that may enhance synergy with immunotherapies, and have synthesized a hypothetical cell signaling and interaction diagram. Collectively, this work provides a foundation for future experimental validation and therapeutic development.
