Qinggan Lidan Capsule attenuates Acetaminophen-induced liver injury by inhibiting the HIF-1α signaling to alleviate mitochondrial damage-triggered hepatocyte apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Acetaminophen-induced liver injury (AILI) is the leading cause of drug-induced liver injury (DILI) worldwide, posing significant clinical challenges. Qinggan Lidan Capsule (QGLDC), a traditional Chinese medicine formula used for jaundice and hepatobiliary disorders based on its heat-clearing and bile-promoting effects, has unexplored therapeutic potential against AILI, warranting investigation.

AIM OF THE STUDY: This study was designed to evaluate the therapeutic potential of QGLDC in AILI and to decipher its underlying hepatoprotective mechanisms.

METHODS

The hepatoprotective effects of QGLDC against AILI were evaluated in vivo and in vitro. To explore the underlying mechanism, key pathophysiological indicators were first assessed. Subsequently, active serum components were identified by HPLC-MS/MS, and the underlying mechanism was predicted by network pharmacology and validated using HIF-1α inhibitors PX-478 and activators DMOG.

RESULTS

Treatment with QGLDC led to a marked amelioration of AILI, evidenced by a substantial reduction in histological injury and oxidative stress, concomitant suppression of inflammatory responses, safeguarding of mitochondrial integrity, and inhibition of hepatocyte apoptosis. Thirty key bioactive components of QGLDC were detected in serum, suggesting their potential roles in mediating the observed hepatoprotection. Mechanistic studies revealed that QGLDC alleviated hepatocyte apoptosis triggered by APAP-induced mitochondrial damage through inhibiting the aberrant overactivation of the HIF-1α signaling.

CONCLUSION

These findings demonstrate that QGLDC alleviates hepatocyte apoptosis triggered by APAP-induced mitochondrial damage through inhibiting the aberrant activation of the HIF-1α signaling. This study underscores the promising therapeutic potential of QGLDC for mitigating DILI and provides a compelling rationale for its clinical development.