Curcumin has been shown to be effective in inhibiting the progression of NAFLD–LF–HCC at doses of 100–400 mg/kg over a 4–8 weeks duration with significant hepatoprotective effects, and its therapeutic mechanisms are related to multiple pathways, including anti-inflammatory, antioxidant, and apoptotic regulations, such as TLR4/NF-κB, Keap1/Nrf2, Bax/bcl2/Caspase3, and TGF-β/Smad3 signaling pathways, which are regulated in all stages of liver disease. The gene discussed is SMAD3; the disease is metabolic dysfunction-associated steatotic liver disease.