Harnessing autophagy-dependent ferroptosis: Mechanisms and therapeutic opportunities in human diseases.

Abstract

Ferroptosis represents an iron-dependent form of cell death driven by lipid peroxidation. Autophagy is an evolutionarily conserved lysosomal degradation pathway, and its dysregulation may trigger or facilitate cell death. Autophagy-dependent ferroptosis (ADF) denotes a specific subtype of ferroptosis executed via selective autophagy, which proceeds by boosting labile iron liberation, accelerating lipid peroxidation, and disrupting cellular antioxidant defense systems. Multiple selective autophagic cascades-including ferritinophagy, lipophagy, mitophagy, clockophagy, as well as autophagic turnover of ferroptosis-associated regulators-modulate cellular vulnerability to ferroptosis in distinct manners. Consistently, ADF exhibits strong context-dependent effects: its activation may eliminate iron-dependent malignant cells, yet over-activation aggravates damage to vital functional cell populations such as neurons, cardiomyocytes, and renal tubular epithelial cells. In this review, we summarize the molecular mechanisms and disease-specific functions of ADF, with a special focus on small-molecule modulators. We construct a target-cell-oriented pharmacological map that integrates their autophagic targets, ferroptotic effects, disease contexts and relevant target-cell populations. Furthermore, we put forward a translational framework incorporating target-cell type, selective-autophagy branch, dose-dependent responses and therapeutic window, thereby providing a rationale for developing ADF-based therapeutic strategies with defined indications, measurable pharmacodynamic biomarkers and controllable toxicity.