Ferroptosis-Mitochondrial Crosstalk in Cardiomyocyte Death: The Cardiomyocyte Ferroptotic Amplification Circuit (CFAC) as a Proposed, Testable Systems Framework.

Cardiomyocyte loss in heart failure is conventionally attributed to apoptosis and necrosis, yet neither fully accounts for the metabolic signature, irreversibility, or magnitude of cell loss in ischemia-reperfusion injury, diabetic cardiomyopathy, or pressure-overload failure. Ferroptosis and mitochondrial dysfunction each contribute to cardiac injury, but their mechanistic interdependence has not been formally modeled. We propose, explicitly as a hypothesis-generating model rather than an established mechanism, the Cardiomyocyte Ferroptotic Amplification Circuit (CFAC), in which ferroptosis and mitochondrial dysfunction are reciprocally reinforcing rather than parallel. CFAC comprises three interlocked positive-feedback loops: an inorganic loop (mitochondrial iron → Fenton ROS → Fe-S cluster disassembly → labile iron); an organic loop (mitochondrial ROS → PE-PUFA peroxidation → electron transport chain adduction → ROS); and a proposed proteotoxic loop (phospholipid hydroperoxide accumulation → hypothesized GPX4 inactivation by electrophilic lipid-peroxidation products → further peroxide accumulation). We postulate that cyclophilin D-regulated permeability transition marks a terminal tipping point at which loss of membrane potential and matrix glutathione extinguishes residual GPX4 activity. The model predicts that partial suppression of two or more loops may outperform complete blockade of one loop, and defines a candidate CFAC-active cardiac phenotype, which requires prospective validation and is proposed neither as a diagnostic entity nor as a distinct cardiomyopathy. Individual components are supported by published experimental work; their integration into a single coupled, nonlinear, threshold-dependent circuit is our inference and is presently unproven. Bistability in the strict sense (two stable states with a hysteretic return path) is a proposed property of that circuit that has not been demonstrated in any system; the framework is therefore described throughout as a proposed nonlinear threshold model, and the experiment that would test bistability directly is specified in Sect. 8.5. The framework is accordingly stated as three nested claims of decreasing security, namely a coupled and threshold-dependent circuit, a bistable and hysteretic extension of it, and a translational phenotype hypothesis, each with its own prespecified falsification criterion, so that a negative result identifies which claim it has ended (Sect. 8.1). We therefore present CFAC as a falsifiable framework and specify the experiments that would confirm or refute it.