Induced pluripotent stem cell (iPSC) therapy brings great hope to the treatment of myocardial injuries, while extracellular vesicles may be one of the main mechanisms of its action. iPSC-derived small extracellular vesicles (iPSCs-sEVs) can carry genetic and proteinaceous substances and mediate the interaction between iPSCs and target cells. In recent years, more and more studies have focused on the therapeutic effect of iPSCs-sEVs in myocardial injury. IPSCs-sEVs may be a new cell-free-based treatment for myocardial injury, including myocardial infarction, myocardial ischemia–reperfusion injury, coronary heart disease, and heart failure. In the current research on myocardial injury, the extraction of sEVs from mesenchymal stem cells induced by iPSCs was widely used. Isolation methods of iPSCs-sEVs for the treatment of myocardial injury include ultracentrifugation, isodensity gradient centrifugation, and size exclusion chromatography. Tail vein injection and intraductal administration are the most widely used routes of iPSCs-sEV administration. The characteristics of sEVs derived from iPSCs which were induced from different species and organs, including fibroblasts and bone marrow, were further compared. In addition, the beneficial genes of iPSC can be regulated through CRISPR/Cas9 to change the composition of sEVs and improve the abundance and expression diversity of them. This review focused on the strategies and mechanisms of iPSCs-sEVs in the treatment of myocardial injury, which provides a reference for future research and the application of iPSCs-sEVs.

Background: Hepatic Ischemia-Reperfusion Injury (IRI) is a critical complication in liver transplantation and resection, driven by oxidative stress and sterile inflammation mediated by damage-associated molecular patterns (DAMPs). Current therapeutic challenges arise from interconnected cell death pathways and redundant inflammatory mechanisms. Objective: This review synthesizes mechanistic insights into DAMP signaling and regulated cell death modalities in IRI, aiming to identify translational gaps and propose precision-targeted therapies. Methods: A literature search in PubMed using keywords “IRI,” “DAMPs,” and cell death modes was conducted without date restrictions. Peer-reviewed studies on human/animal models were included, with qualitative synthesis of DAMP-cell death interactions. Results: During ischemia, mitochondrial dysfunction releases HMGB1, ATP, and mtDNA, activating Kupffer cell TLR4/RAGE and cGAS-STING pathways, triggering NLRP3 inflammasomedriven cytokine storms. Reperfusion amplifies ROS bursts, lipid peroxidation, and iron overload, creating a self-sustaining cycle of damage. Cell death modalities exhibit spatiotemporal specificity: hepatocyte ferroptosis dominates early injury, while macrophage pyroptosis and necroptosis predominate in steatotic livers during late phases. HMGB1 lactylation and mtDNA-cGAS signaling emerge as key regulators. Machine perfusion (e.g., hypothermic oxygenated perfusion) reduces biliary complications via mitochondrial resuscitation, outperforming conventional drugbased therapies. Conclusion: Current single-pathway targeting shows limited efficacy due to IRI’s complexity. Future strategies should integrate temporal targeting (ferroptosis inhibitors pre-reperfusion; pyroptosis blockers post-reperfusion), DAMP-neutralizing agents (anti-HMGB1 antibodies), and precision preservation combining multi-omics biomarkers with ex vivo pharmacological preconditioning. Addressing metabolic vulnerabilities in fatty livers and refining cell death-specific interventions are critical for bridging translational gaps.

Diabetes mellitus (DM) is increasing rapidly worldwide, and diabetic cardiomyopathy (DCM) has become a leading cause of death in diabetic patients. Therefore, effective strategies for the prevention and treatment of DCM are urgently needed. Ferroptosis, a form of regulated cell death, has been implicated in the pathogenesis of DCM. This study integrated network pharmacology, data mining, molecular docking, molecular dynamics simulations, and in vitro experiments to investigate whether baicalein inhibits high glucose and sodium palmitate (HG + PA)-induced ferroptosis in cardiomyocytes and to elucidate the underlying mechanisms. Baicalein significantly improved the viability of H9c2 and AC16 cells, reduced cell death, and decreased LDH release under HG + PA conditions. Network pharmacology predicted that the protective effects of baicalein against HG + PA-induced cardiomyocyte injury were associated with ferroptosis regulation. Transcriptomic data mining further identified ferroptosis-related pathway enrichment in complementary in vitro and diabetic rat cardiac datasets. Molecular docking predicted favorable binding poses of baicalein with Nrf2, SLC7A11, and GPX4, while molecular dynamics simulations suggested general stability of the modeled complexes. In vitro experiments further confirmed ferroptosis involvement, as the ferroptosis inhibitor Ferrostatin-1 (Fer-1) reversed the HG + PA-induced decline in cell viability. Conversely, the ferroptosis inducer Erastin diminished cell survival and antagonized the protection conferred by baicalein, indicating that baicalein acts by inhibiting ferroptosis. Baicalein reduced lipid peroxidation, MDA and Fe²⁺ levels, and the mRNA expression of ACSL4 and PTGS2, while restoring the GSH/GSSG ratio and the protein expression of Nrf2, SLC7A11, and GPX4. These protective effects were partially reversed by the Nrf2 inhibitor ML385. In conclusion, baicalein protects cardiomyocytes from HG + PA-induced injury by activating the Nrf2/SLC7A11/GPX4 signaling pathway and inhibiting ferroptosis.