Crosstalk of regulated cell death pathways in sepsis-associated acute kidney injury: implications for therapy.

Sepsis-associated acute kidney injury (SA-AKI) is a common and severe complication in critically ill patients, independently associated with significantly increased mortality and a high risk of progression to chronic kidney disease. The pathogenesis of SA-AKI is complex and involves not only traditional concepts such as renal hypoperfusion, microcirculatory dysfunction, and direct tubular injury, but also, more importantly, the disordered activation of the host immune response. In recent years, regulated cell death (RCD) has emerged as a central mechanism linking immune dysregulation to tissue damage in SA-AKI. Unlike accidental cell death, RCD is orchestrated by genetically encoded molecular machinery, offering potential targets for therapeutic intervention. This review systematically summarizes the distinct molecular mechanisms of five major RCD pathways, including apoptosis, pyroptosis, necroptosis, autophagy, and ferroptosis, in the pathogenesis of SA-AKI. We highlight the specific contributions of each pathway, their regulatory networks, and the critical molecular players involved. Importantly, we delve into the intricate crosstalk among these pathways, such as caspase-8 acting as a molecular switch between apoptosis, pyroptosis, and necroptosis, the synergistic interplay between Gasdermin D and mixed lineage kinase domain-like protein, the role of autophagy as a "gatekeeper" for other RCDs, the concept of ferritinophagy, and the shared upstream signals including pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), Toll-like receptor 4 (TLR4), and oxidative stress. Building upon this mechanistic framework, we further evaluate the current state and future potential of targeted therapeutic strategies aimed at modulating RCD pathways to mitigate renal injury in sepsis. Thus, this review pursues two complementary objectives: to provide a cohesive mechanistic synthesis of RCD crosstalk in SA-AKI, and to propose a theoretical foundation for developing novel, multi-targeted therapies.