Targeting integrated cell death networks in sepsis-associated acute kidney injury: Shared regulatory nodes and diet-related small molecule modulation (Review)

Abstract

Sepsis-associated acute kidney injury (SA-AKI) presents a significant challenge in critical care, largely due to the multifaceted nature of renal injury stemming from interconnected disturbances in inflammation, metabolism, microcirculation, mitochondrial function and programmed cell death, rather than arising from a singular dominant pathway. Increasing evidence indicates that apoptosis, pyroptosis, ferroptosis, necroptosis and autophagy-related responses function as an integrated yet heterogeneous cell death network, characterized by extensive crosstalk, compensatory signaling and disease stage-dependent regulation. The present review uses an integrated cell death network framework for SA-AKI, rather than simply summarizing individual cell death pathways or sequentially cataloguing diet-related small molecules. Current evidence was synthesized by organizing shared regulatory nodes according to their mechanistic roles, including upstream drivers, amplifiers or permissive states, context-dependent modifiers, and terminal execution mechanisms. Focus is placed on mitochondrial dysfunction, redox-iron imbalance, NF-κB-dependent inflammatory activation, inflammasome priming, failures in autophagy/mitophagy and immunometabolic stress. Furthermore, the present review explores how diet-related small molecules may influence these shared injury conditions, differentiating between food-derived phytochemicals, nutritional compounds, microbiota-derived metabolites and intensive care unit-based antioxidant or vitamin regimens. The potential efficacy of these compounds may derive less from their ability to selectively inhibit isolated death programs and more from their capacity to reshape common upstream environments that allow multiple death pathways to manifest. Finally, major translational barriers are discussed, including limited bioavailability, uncertainty surrounding active metabolites, altered pharmacokinetics during sepsis, disease-stage specificity, renal target exposure and inter-patient heterogeneity. An exposure-aware and endotype-guided framework is proposed for the future evaluation of diet-related small molecules in the context of SA-AKI.