epsis is a life-threatening syndrome characterized by acute organ dysfunction resulting from a dysregulated host response to infection. Despite advances in antimicrobial therapy, source control, hemodynamic resuscitation, and organ-supportive strategies, sepsis continues to be associated with substantial morbidity and mortality. Current management is primarily supportive and does not directly target the interconnected processes of excessive inflammation, oxidative stress, endothelial dysfunction, and cellular injury that contribute to progressive organ dysfunction. Current international guidance emphasizes prompt antimicrobial therapy, source control, hemodynamic resuscitation, lactate assessment, and appropriate organ support as the foundation of management.
Oxidative stress is an important component of sepsis pathophysiology. Excessive production of reactive oxygen species, together with impaired endogenous antioxidant defenses, can promote lipid peroxidation, mitochondrial dysfunction, cellular injury, and amplification of inflammatory signaling. Maladaptive activation of inflammatory pathways, including nuclear factor-kappa B (NF-κB), contributes to increased production of pro-inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). These processes may contribute to dysfunction of the kidney, liver, lungs, cardiovascular system, and other organs.
Ursodeoxycholic acid (UDCA) is a hydrophilic endogenous bile acid with an established clinical safety record and established hepatobiliary therapeutic use. Beyond its conventional hepatoprotective effects, experimental evidence suggests that UDCA may exert antioxidant, anti-inflammatory, anti-apoptotic, cytoprotective, and mitochondrial effects.
The rationale for investigating UDCA in sepsis is supported by several lines of evidence. Experimental work has demonstrated that UDCA can attenuate sepsis-induced acute kidney injury through activation of the Nrf2/HO-1 antioxidant pathway and inhibition of NF-κB signaling, accompanied by reductions in TNF-α, IL-1β, IL-6, and renal injury markers. Experimental studies have also demonstrated attenuation of sepsis-associated lung injury, pulmonary barrier dysfunction, oxidative stress, inflammatory cytokine production, and PANoptosis following UDCA administration.
Importantly, emerging clinical evidence has begun to investigate UDCA in adult sepsis. A retrospective matched study of critically ill adults with sepsis/septic shock did not demonstrate significant improvement in day-3 SOFA score or vasopressor requirements, although improvement in the PaO₂/FiO₂ ratio and earlier extubation were observed among UDCA recipients. More recently, a small prospective pilot involving eight septic patients receiving UDCA explored its potential effects on sepsis-associated platelet dysfunction, while mechanistic studies implicated TREM2-linked signaling.
Therefore, a randomized controlled trial is warranted to determine whether adjunctive UDCA can modify the biological abnormalities underlying sepsis, particularly oxidative stress and inflammation, and whether these effects are accompanied by improvement in organ dysfunction.