Edible Fungus Compound Cordycepin Protects Against Acetaminophen-Induced Liver Injury

Medicinal-edible natural products like Cordyceps militaris (C.militaris), a functional food rich in cordycepin (COR), are promising for health maintenance. Although COR possesses anti-inflammatory and antioxidant properties, its protective efficacy and underlying mechanisms against acetaminophen (APAP)-induced hepatotoxicity remain unclear. This study aimed to evaluate the influence of COR pretreatment on APAP-induced acute liver injury and elucidate the underlying mechanisms.

To this end, male C57BL/6 mice were gavaged for 7 days with NAC (N-acetylcysteine) (200 mg/kg) or COR (50, 100, or 200 mg/kg), followed by APAP administration (400 mg/kg, gavage) to cause liver injury for 12 h. Liver injury was evaluated by serum transaminase levels, histopathological analysis, inflammatory cytokine detection, oxidative stress markers, TUNEL staining, and RNA-seq-based transcriptomic analysis.

COR pretreatment markedly reduced serum transaminases and alleviated hepatic necrosis and inflammatory infiltration. RNA-seq revealed significant APAP-induced changes in genes associated with ER protein processing, HIF-1, and PPAR signaling, while COR reversed multiple key genes involved in oxidative stress, inflammation, and apoptosis. Consistent with transcriptomic findings, COR decreased pro-inflammatory cytokines, mitigated oxidative damage, and inhibited hepatocyte apoptosis (TUNEL staining).

In conclusion, COR pretreatment attenuates APAP-induced hepatotoxicity in mice by modulating ER proteostasis-related pathways and coordinately influencing HIF-1 and PPAR-associated signaling networks, thereby exerting anti-inflammatory, antioxidant, and anti-apoptotic effects. These findings support COR as a promising hepatoprotective candidate for APAP-caused liver damage.