This research investigated whether Lactobacillus plantarum KSFY06 (LP-KSFY06) could prevent acute liver damage caused by combined D-galactose and lipopolysaccharide (D-Gal/LPS) exposure in mice. The antioxidant activity of LP-KSFY06 was first examined using in vitro radical scavenging assays. In mice, the effects on liver injury were assessed through organ weight indices, serum liver function markers, oxidative stress parameters, inflammatory cytokines, gene expression levels, and histological examination of liver tissue. LP-KSFY06 demonstrated strong free radical scavenging capacity against DPPH and ABTS in vitro. In vivo, mice pretreated with LP-KSFY06 showed improved liver histology and organ indices, indicating reduced tissue injury. The treatment preserved antioxidant enzyme activities, including SOD, GSH, GSH-Px, CAT, and total antioxidant capacity, and inhibited the elevation of AST, ALT, MDA, MPO, and NO induced by D-Gal/LPS. LP-KSFY06 also shifted the inflammatory balance by increasing the anti-inflammatory cytokine IL-10 and suppressing pro-inflammatory cytokines IL-6, IL-1β, TNF-α, and IFN-γ, consistent with observed changes in gene expression. Mechanistically, LP-KSFY06 downregulated the expression of Keap1, NLRP3, ASC, caspase-1, NF-κB, IL-18, and p38 MAPK, while upregulating Nrf2, HO-1, NQO1, IκB-α, and Trx, suggesting involvement of the Keap1–Nrf2/ARE and NLRP3/NF-κB pathways in its hepatoprotective action. LP-KSFY06 functions as a multifunctional probiotic with strong antioxidant and anti-inflammatory effects, providing effective protection against D-Gal/LPS-induced acute liver injury and supporting liver health in mice.
