Aging promotes ferroptosis in zone 3 hepatocytes, yet the upstream trigger that makes pericentral cells uniquely susceptible remains undefined. We hypothesize that chronic pericentral hypoxia, amplified by age‑related mitochondrial dysfunction, stabilizes HIF‑1α in zone 3 hepatocytes. HIF‑1α directly transcriptionally up‑regulates transferrin receptor (Tfrc) and acyl‑CoA synthetase long‑chain family member 4 (ACSL4), increasing labile iron and polyunsaturated fatty‑acid activation. Simultaneously, HIF‑1α induces microRNA‑210, which suppresses glutathione peroxidase 4 (GPX4) translation, weakening the primary lipid‑peroxide detoxification system. The convergence of heightened iron import, enhanced PUFA‑CoA synthesis, and reduced GPX4 activity creates a permissive environment for lipid peroxidation, driving ferroptosis and the ferrosenescence signature (AHGS) observed in aged MASLD livers.

This mechanism integrates three layers of the existing data: (1) the zone‑3 enrichment of Tfrc, ACSL4, and lipid peroxidation markers reported in the AHGS [1]; (2) the strong correlation of AHGS with metabolic stress, BMI, and type 2 diabetes, which exacerbate hepatic hypoxia and HIF‑1α activation [2]; and (3) the efficacy of ferroptosis inhibition (ferrostatin‑1) in reversing age‑exacerbated MASH, suggesting that blocking the downstream consequence of HIF‑1α‑driven iron overload is therapeutic [1,3].

Testable predictions:

1. In young and old mice fed a choline‑deficient, high‑fat diet, immunofluorescence will show higher nuclear HIF‑1α, Tfrc, and ACSL4, and lower GPX4 specifically in pericentral (glutamine synthetase‑positive) hepatocytes of old mice; zone 1 hepatocytes will show no significant change.
2. Genetic hepatocyte‑specific Hif1a knockout or pharmacological HIF‑1α inhibition (e.g., PX‑478) in old MASLD mice will reduce Tfrc and ACSL4 expression, restore GPX4 activity, lower lipid peroxidation (MDA/4‑HNE), and decrease AHGS‑positive hepatocytes to levels comparable to young controls.
3. Combining HIF‑1α inhibition with ferrostatin‑1 will produce additive protection against fibrosis (hydroxyproline content) and SASP cytokine secretion (TNFα, IL‑6) compared with either monotherapy.
4. Primary human zone 3‑enriched hepatocyte isolations from lean versus obese donors will display inverse correlations between HIF‑1α target scores and GPX4 protein, with the strongest association in donors >50 years or with type 2 diabetes.

Falsification would occur if HIF‑1α manipulation fails to alter Tfrc/ACSL4/GPX4 or ferroptosis markers in zone 3 hepatocytes, or if AHGS persists despite normalized HIF‑1α activity, indicating that pericentral hypoxia‑HIF‑1α signaling is not the primary driver of zone‑3‑selective ferroptosis in aging MASLD.