Withania somnifera ameliorates endoplasmic reticulum stress in human hepatocellular carcinoma HepG2 cells

Endoplasmic reticular (ER) stress plays an important role in gene modulation and the consequent release of several inflammatory mediators i.e., cytokines and proteases, key players associated with systemic-induced inflammation in various liver diseases. Natural products containing bioactive compounds have emerged as better therapeutic agents, attributed to their affordability as well as inherent biological properties. Withania somnifera (WS, Ashwagandha) is recognized for its immunomodulatory activities in Ayurveda.

The present study investigated the effects of WS in uninduced and tunicamycin (Tm)-stimulated inflammation as well as ER stress response in HepG2 cells. The cells were optimized for Tm stress induction time, concentration as well as treatment mode (pre-, co- or post-).

There was a substantial increase in ER stress and inflammation response after 24 h at 40 μg/mL in the pretreatment group. WS treatment significantly inhibited ER stress response and inflammation in uninduced and Tm-induced stress groups in a dose-dependent approach. The activation of PERK/eIF2α/ATF4 and IRE1α/JNK signaling cascades was inhibited by WS in both uninduced and Tm-stimulated cells. The molecular pathways involved in suppression of hepatic inflammation included NF-κB, P38 and MAPK JNK which showed inhibition by WS. Suppression of inflammatory cytokine production viz. IL-1β, IL-6, and IL-18 was observed in both uninduced and stress-induced cells.

This study suggests that WS is a potential candidate to prevent inflammation and ER stress response against ER-stress triggered inflammation in HepG2 ER cells.