Imbalance of the Regulated Cell Death and Autophagic Network: A Core Mechanism Driving Toxicological and Ischemic Myocardial Injury and a Target for Intervention with Traditional Chinese Medicine.

Myocardial injury is a common pathological endpoint in conditions such as acute myocardial infarction, ischemia/reperfusion injury, myocarditis, and drug-induced cardiotoxicity, and remains a therapeutic challenge due to the irreversible loss of cardiomyocytes and subsequent ventricular remodeling. Current strategies lack effective interventions directly targeting regulated cell death pathways. This review centers on the dysregulation of the regulated cell death (RCD) and autophagic network. We comprehensively integrate the dual roles, and evidence-graded crosstalk among RCD modalities (apoptosis, pyroptosis, and ferroptosis) and autophagic responses, proposing a paradigm shift from isolated pathway inhibition to dynamic rebalancing of the RCD and autophagic network for cardioprotection. Within this framework, we consolidate and compare evidence illustrating how active metabolites, single botanical drugs, and compound formulations of traditional Chinese medicine regulate multiple forms of RCD-associated signaling and autophagic processes. The multi-metabolite, multi-target nature enables coordinated regulation at the cellular survival-death checkpoint. Mechanistically, TCM interventions can: (1) attenuate apoptotic marker expression and context-dependently modulate autophagic responses via axes such as PI3K/Akt/mTOR, AMPK/mTOR, MAPK, and JAK/STAT; (2) suppress NLRP3/caspase-1/GSDMD-mediated pyroptotic signaling markers; and (3) modulate lipid peroxidation-associated ferroptotic signaling through antioxidant pathways centered on the Nrf2/GPX4 and System xc⁻ axes. These actions collectively ameliorate upstream pathological loops involving oxidative stress, inflammatory amplification, and mitochondrial dysfunction. This review adopts a comprehensive cardiovascular toxicology perspective to integrate the regulatory mechanisms of RCD and autophagic networks in myocardial injury, encompassing both exogenous drug-induced cardiotoxicity (e.g., doxorubicin) and endogenous toxic stresses, including lipotoxicity, ROS-mediated toxicity, and ischemia-related metabolic injury. Notably, many TCM agents exhibit cross-RCD and autophagic synergistic effects supported by direct perturbation-and-rescue evidence (Level c crosstalk) as well as co-regulatory profiles, suggesting that cardioprotection at the network level may be achieved through shared hub nodes. This perspective provides a clearer mechanistic landscape for elucidating the action of TCM formulas and for screening novel therapeutic candidates. Ultimately, it advocates for advancing traditional Chinese medicine-based myocardial protection strategies into reproducible, quantifiable, and clinically verifiable pharmacological research systems oriented around RCD and autophagic network homeostasis.