Schisandrin B protects against oxaliplatin-induced liver injury by suppressing ferroptosis via the canonical KEAP1-Nrf2 and non-canonical microbiota-driven Lactobacillus reuteri-CLA-Nrf2 axes.

Ferroptosis is a critical contributor to chemotherapy-induced liver injury. Schisandrin B (SchB), a bioactive compound from Schisandra chinensis, exerts hepatoprotection, but the underlying mechanisms in oxaliplatin (OXA)-induced liver injury are unclear. In this study, OXA treatment induced hepatic dysfunction, lipid accumulation, and gut dysbiosis, with marked depletion of Lactobacillus reuteri (L. reuteri). A lipidomic analysis showed that SchB reversed OXA-induced linoleic acid (LA) metabolic reprogramming, particularly PE (18:0_18:2) and PE (18:2_18:2) accumulation. A targeted quantification revealed that OXA increased the levels of the LA-derived oxidation products 9-HODE and 13-HODE, which were significantly reduced by SchB treatment. Mechanistically, SchB mitigated OXA-induced DILI by suppressing ferroptosis through the dual-targeted activation of Nrf2. Notably, in addition to the canonical KEAP1-dependent mechanism, an important gut microbiota-mediated pathway appeared to contribute substantially to Nrf2 activation. SchB reshaped the gut microbiota by enriching L. reuteri, which metabolized the accumulated LA into conjugated linoleic acid (CLA). The CLA contributed to Nrf2 activation via a microbiome-dependent non-canonical pathway. Nrf2 knockout rats and FMT experiments further confirmed the causal roles of Nrf2 and L. reuteri in SchB-mediated hepatoprotection against lipid peroxidation. Importantly, in microbiota-depleted rats with OXA-induced liver injury, CLA supplementation partially restored Nrf2 activation and attenuated lipid peroxidation, indicating that CLA positively affected the microbiota-dependent hepatoprotective pathway associated with SchB. Collectively, these findings identify SchB as a potent therapeutic candidate against OXA-induced liver injury and highlight a microbiota-driven L. reuteri-CLA-Nrf2 axis as a key non-canonical pathway regulating gut-liver metabolic crosstalk and ferroptosis to maintain hepatic homeostasis.