Kinsenoside derivatives mitigate acute liver injury in mice via MAPK pathway-mediated oxidative stress suppression

Acute liver injury (ALI), primarily induced by drugs and toxins, is characterized by rapid progression and high mortality. The lack of effective therapeutic agents presents a serious clinical challenge, underscoring the urgent need for novel drug development. Herein, we report two novel kinsenoside (KD) derivatives, KCM and KCF, synthesized via a two-step chemical strategy, which exhibit potent hepatoprotective effects in acetaminophen (APAP)- and thioacetamide (TAA)-induced ALI mouse models. Both compounds demonstrated superior hepatoprotection, normalizing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, attenuating the inflammatory cascade and histopathological damage to an extent comparable to the clinical antioxidant N-acetylcysteine (NAC). Time-resolved analysis reveals a sequential therapeutic mechanism, where early mitogen-activated protein kinases (MAPK) pathway inhibition (within 2 h) precedes downstream ferroptosis and inflammation blockade, demonstrating a temporally orchestrated protective cascade. Mechanistically, KCM and KCF mitigate APAP- and TAA-induced oxidative stress primarily by dampening MAPK signaling, thereby blocking lipid peroxidation, ferroptosis, and pro-inflammatory pathways. This multilayered intervention ultimately halts ALI progression, underscoring their hepatoprotective potential. Collectively, our findings indicate that KCM and KCF exert hepatoprotective effects primarily through inhibition of MAPK, highlighting their potential as therapeutic agents for ALI and warranting further investigation.