• PNX-14 alleviates HFD-induced obesity and fatty liver.• It reduces elevated ALT, AST, total cholesterol, and triglycerides levels.• PNX-14 increases hepatic SOD activity and GSH production while reducing MDA activity.• It decreases the production of pro-inflammatory cytokines TNF-α and IL-6.• The protective effects of PNX-14 are likely mediated through the activation of the SIRT1/AMPK and NRF2/HO-1 pathway. This evidence concerns the gene GPT and obesity due to melanocortin 4 receptor deficiency.