The dual role of nicotine in the development and progression of hepatocellular carcinoma

Nicotine is a significant regulator of cellular signaling pathways in the development of hepatocellular carcinoma (HCC). Also, it can activate intracellular signaling pathways leading to apoptosis in HCC. However, a comprehensive overview exploring the mechanisms linking HCC and nicotine is currently lacking. In this review, we examined the emerging evidence of the relationship between the development and progression of HCC and nicotine. Firstly, nicotine primarily promotes HCC through the activation of various cellular pathways, including α7-nicotinic acetylcholine receptor (nAChR)/janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (STAT3) pathway, cytochrome P450 (CYP) 1A1/protein kinase B (Akt) signaling activated by nuclear factor-κB (NF-κB) and activating protein-1 (AP-1), SET domain bifurcated 1 (SETDB1) and cyclin-dependent kinase 6 (CDK6)-mediated stability of STAT1, GC-rich binding factor 2 (GCF2)-mediated wingless int(Wnt)/β-catenin/sex-determining region Y-box 2 (SOX2) pathway, and β2-adrenergic receptor (β2-AR)/phosphoinositide 3-kinase (PI3K)/Akt signaling. Conversely, nicotine's inhibitory effects on HCC development may be mediated through the activation of signaling pathways. For instance, nicotine can stimulate immature dendritic cells to enhance immune response via PI3K/Akt pathway, as well as mediate the expressions of caspase-3 and Cyclin B1 via α7-nAChR. We reviewed the toxicological and pharmacological effects and related mechanisms of nicotine. It revealed that nicotine's impact on the liver is intricate and often conflicting. Nicotine may potentially fuel tumorigenesis through cellular processes. So, smoking cessation and protection from nicotine's effects are crucial. While recognizing potential benefits of nicotine on inflammation, it does not condone smoking; exploring its products for HCC therapy can advance treatment understanding.