Hepatic p38γ exacerbates acetaminophen‑induced acute liver injury via PI3K/Akt‑dependent mechanisms.

An acetaminophen (APAP) overdose can result in acute and chronic liver injury. Thus, the discovery of biomarkers for the management of APAP‑induced liver injury is crucial from a therapeutic standpoint. As one of the four isoforms of p38 mitogen activated protein kinases, p38γ plays a notable role in the inflammatory processes associated with various diseases. However, the underlying molecular mechanisms of p38γ in liver injury are largely unknown. In the present study, it was demonstrated that AML‑12 cells and liver tissues induced with APAP had elevated p38γ expression. DCFH‑DA fluorescent probe and oil red O staining was used to investigate oxidative stress and lipid metabolism in APAP‑induced AML‑12 cells and western blotting was used to assess the expression levels of oxidative stress and lipid metabolism‑related protein inflammatory cytokines. The results showed that p38γ knockdown significantly attenuated the inflammatory response, oxidative stress and lipid accumulation, whereas overexpression of p38γ exhibited the opposite effect. Downstream, p38γ induced the activation of the PI3K/Akt signaling pathway via upregulation of phosphorylated (p‑)PI3K and p‑Akt levels. Additionally, TargetScan analysis and dual luciferase reporter assays showed that microRNA‑125 selectively targeted the 3'‑untranslated region of p38γ, resulting in the repression of APAP‑induced inflammation, lipid accumulation and oxidative stress. Furthermore, adeno‑associated virus 9‑short hairpin RNA p38γ was used via tail vein injection to cause p38γ downregulation