Modulation of the Nrf2/Keap1 Pathway by N-Acetylcysteine: A Key Mechanism in the Prevention of Experimental Hepatocellular Carcinoma
Background & Aims: Hepatocellular carcinoma (HCC) is the most common primary liver cancer, marked by dysregulated cellular processes and limited treatment options. N-acetylcysteine (NAC), widely used for acetaminophen overdose and as a mucolytic agent, has not been mechanistically characterized in HCC. We evaluated the effects of NAC in experimental HCC, including its role in modulating the Nrf2/Keap1 signaling pathway Methods: HCC was induced in male Fischer-344 rats using diethylnitrosamine (DEN) and 2-acetylaminofluorene (2-AAF), with daily NAC administration for 16 weeks. In parallel, HepG2 cells were used to evaluate the cytoprotective effects of NAC in vitro. Biochemical, molecular, transcriptomic, and histological analyses were performed. Results: NAC exerted hepatoprotective effects that limited protumorigenic progression, fibrosis, and tumor cell proliferation. Notably, NAC modulated the Nrf2/Keap1 pathway, enhancing antioxidant defenses and preserving biomolecular integrity. Conclusions: NAC modulates key cellular processes involved in HCC development, supporting its repositioning as a potential adjuvant therapeutic strategy. Overall design: HCC was induced using an established experimental model (Castro-Gil MP, et al 2021). Eighteen male Fischer-344 rats (˜180g) were randomized into three groups. CTL: receiving 0.5% (w/v) carboxymethyl cellulose (CMC, p.o., daily). HCC: receiving DEN (50 mg/kg, i.p., weekly), followed by 2-AAF (25 mg/kg, p.o.). HCC/NAC: receiving the same treatments as the HCC group, plus NAC (300 mg/kg, p.o., daily). Liver injury was induced for 16 weeks