Vitamin D/VDR Signaling and Programmed Cell Death in Sepsis-Associated Organ Injury: Evidence from Sepsis and Related Disease Models.

Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection and is frequently complicated by multi-organ dysfunction. Current management relies primarily on timely antimicrobial therapy, source control, hemodynamic resuscitation, and organ support, whereas effective therapies that directly target programmed cell death (PCD) involved in sepsis-associated organ injury remain lacking. Recent evidence indicates that, beyond its classical role in mineral metabolism, vitamin D (VD) and the vitamin D receptor (VDR) are involved in the regulation of immune homeostasis, oxidative stress, and cellular fate. This review summarizes current advances in the protective effects of VD/VDR against organ injury through the modulation of PCD and discusses the mechanisms by which VD/VDR regulates PCD pathways in relevant non-septic disease contexts. We further synthesize the available evidence supporting the involvement of VD/VDR signaling in the regulation of major PCD pathways, including apoptosis, pyroptosis, and ferroptosis, during sepsis-associated organ injury. Collectively, these findings suggest that VD/VDR signaling may serve as a systemic modulator of interconnected PCD networks and represent a potential adjunctive therapeutic target in sepsis. However, direct mechanistic evidence from clinically relevant sepsis models remains limited, and substantial preclinical and clinical investigation is still required before VD/VDR-targeted interventions can be established as a therapeutic strategy for sepsis.