Ferroptotic memory of the peritoneal niche: Mechanisms, cross-disease and cardiovascular-reproductive parallels, and targetable vulnerabilities

Menstrual retrograde hemorrhage deposits heme-rich, erythrocyte-laden fluid into the peritoneal cavity, creating a spatially concentrated and recurring source of labile Fe(II) that is chemically poised to catalyze Fenton chemistry and seed polyunsaturated-lipid peroxidation. Current human and experimental data document co-occurrence of peritoneal iron accumulation, oxidized phospholipids, platelet activation and neutrophil extracellular traps, but the causal chain that converts cyclical iron exposure into durable tissue reprogramming and lesion persistence remains unresolved. Here we articulate a unifying, testable model in which repeated menstrual iron pulses act as a patterned biological signal that (i) supplies PUFA substrates and redox-active cofactors via platelets and platelet-derived microparticles, (ii) concentrates oxidant enzymes on NET-anchored scaffolds to amplify local peroxidation, and (iii) engages intracellular iron-sensitive dioxygenases and lipid-remodelling enzymes to rewire chromatin, metabolism and ferroptotic susceptibility in resident immune and stromal cells. To close the central causality gaps we propose a structured validation pipeline that combines orthogonal genetic (cell-type restricted GPX4/ACSL4 perturbations), pharmacologic (radical-trapping antioxidants and iron chelators), temporal lipidome→phenotype time-series, high-resolution spatial lipidomics, and rigorous vesicle transfer/neutralization tests; each mechanistic arm is explicitly linked to translational biomarkers (oxidized PE/PC panels, labile iron assays, PMP signatures) to ensure clinical measurability. This framework reframes cyclical hemorrhage not as episodic damage but as a chronic imprinting process that can create ferroptotic "memory", with implications for pain, lesion persistence and fertility, and with mechanistic parallels in hemorrhagic tumor niches, intraplaque hemorrhage and neurohemorrhage. By aligning causal experiments with early-phase trial designs and targeted delivery strategies, the proposed program converts a plausible chemical hypothesis into an intervention-ready research agenda that bridges molecular mechanism to patient-centered outcomes.