Journal Article

Autophagy-ferroptosis crosstalk in sepsis: metabolic pathways, redox injury, and host-directed antioxidant nanomedicine

Feng, Shi, Huang, Yang, Yi, Fan, Gao, Yuhong, Wang, Jiaqi

2026

Overview

Sepsis is a dynamic syndrome of infection-driven metabolic and immune dysregulation in which oxidative stress can escalate into an \"oxidative storm,\" promoting organ dysfunction and maladaptive host responses. Within this context, ferroptosis represents a metabolically constrained form of regulated necrotic cell death driven by iron-dependent lipid peroxidation, linking redox collapse to tissue injury in sepsis. Emerging evidence suggests that autophagy critically shapes ferroptosis susceptibility by regulating intracellular iron mobilization, membrane lipid substrate availability, mitochondrial quality control, and energy-stress signaling. This review therefore frames autophagy-ferroptosis crosstalk in sepsis as a host metabolic vulnerability and discusses how mechanism-guided, host-directed antioxidant nanomedicine may help preserve tissue integrity while limiting interference with antimicrobial defense. We explored how autophagy modulates ferroptosis susceptibility by regulating iron metabolism, lipid substrate availability, and mitochondrial quality control. Building on this framework, we evaluated emerging antioxidant nanomedicines targeting key intervention points, including iron chelation, catalytic ROS/RNS scavenging, membrane-localised radical trapping, mitochondria-targeted source control, and enhancement of endogenous defences. Organ- and immune-specific effects are highlighted, emphasizing the need for aligned biochemical readouts, flux-aware autophagy evaluation, and stage-specific therapeutic targeting. Finally, we outline translational priorities for precision redox modulation in sepsis, focusing on biomarker-guided patient stratification, compartment-specific delivery, and biosafety considerations.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animals / antioxidant nanomedicine / Antioxidants / Antioxidants - pharmacology / Antioxidants - therapeutic use / Autophagy / Autophagy - drug effects / Cell death / Chelation / Ferroptosis / Ferroptosis - drug effects / Glutathione / host-directed therapy / Host-Directed Therapy - methods / Humans / Hydrogen / immunometabolism / Iron / Iron - metabolism / Lipid metabolism / Lipid Peroxidation / Lipids / Membranes / Metabolic Networks and Pathways / Metabolic pathways / Metabolism / Mitochondria / Mitochondria - metabolism / Nanomedicine - methods / Nanotechnology / Nitric oxide / Nosocomial infections / Oxidation / Oxidation-Reduction / Oxidative stress / Oxidative Stress - drug effects / Pathogens / Polyunsaturated fatty acids / Propagation / Quality control / Reactive oxygen species / Review / Sepsis / Sepsis - drug therapy / Sepsis - immunology / Sepsis - metabolism / Therapeutic targets