Dysregulation of xenobiotic metabolism and mitochondrial dysfunction exacerbate acetaminophen-induced hepatotoxicity in human antigen R-deficient male mice

livers, consistent with impaired detoxification and increased APAP-protein adduct formation. Fourier-transform infrared (FTIR) spectroscopy further identified early biochemical alterations between genotypes as early as 2 h after APAP exposure. HuR deficiency also resulted in pronounced mitochondrial structural abnormalities and dysfunction, accompanied by reduced expression of mitochondrial fission and fusion proteins (Drp1 and Mfn2), increased mitochondrial protein release, and enhanced hepatocyte death. Mechanistically, HuR inhibition and overexpression studies demonstrated its regulatory role in genes involved in detoxification and mitochondrial integrity. Ribonucleoprotein immunoprecipitation (RNP-IP) confirmed direct binding of HuR to mRNAs encoding mitochondrial dynamics proteins (Drp1, Mfn2), detoxification enzymes (Gsta4, Gstm6), and antioxidant regulators (Nrf2, Gclc, Gclm). Collectively, these findings identify hepatocyte HuR as a critical regulator of xenobiotic metabolism and mitochondrial function and establish the essential role of HuR in early protection against APAP-induced hepatotoxicity.