Speaker
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Background: Hepatic ischemia‑reperfusion injury (HIRI) remains a major challenge in liver surgery. The pregnane X receptor (PXR) is a key regulator of xenobiotic metabolism and cellular stress responses, yet its role in HIRI is poorly defined. Here, we investigated the function of PXR in both vivo and in vitro models of liver IRI.
Methods: To investigate the role of PXR in hepatic I/R injury, we employed complementary in vivo and in vitro models. A murine HIRI model was established, with mice receiving pretreatment of the PXR agonist PCN or vehicle for three days prior to surgery. In parallel, AML12 and HepG2 cells underwent oxygen‑glucose deprivation/reperfusion (OGD/R) to model I/R stress in vitro.
Results: Hepatic PXR expression was significantly downregulated following in vivo I/R injury, as well as in AML12 and HepG2 cells subjected to OGD/R. Genetic ablation of Pxr in mice exacerbated liver damage and inflammatory responses post‑IRI. Conversely, pretreatment with the PXR agonist PCN markedly ameliorated hepatic injury, reduced serum transaminase levels, and improved histopathological outcomes in wild-type mice subjected to I/R. Mechanistically, PXR‑mediated protective effects depended on HMGCS2. PXR directly interacted with HMGCS2 and stabilized its protein during I/R, thereby preserving hepatic ketogenesis and mitochondrial function.
Conclusions: PXR expression is reduced during HIRI, and its pharmacological activation protects against HIRI by maintaining HMGCS2‑dependent metabolic and mitochondrial homeostasis, highlighting the PXR–HMGCS2 axis as a potential therapeutic target for liver IRI.
