Thioredoxin-Binding protein 2 and apoptosis Signal-Regulating kinase 1: redox stress sensors and therapeutic targets in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) develops under sustained oxidative and inflammatory stress, where thioredoxin-binding protein 2 (TBP2/TXNIP) and apoptosis signal-regulating kinase 1 (ASK1/MAP3K5) act as central redox sensors. Under basal conditions, TBP2 inhibits reduced thioredoxin, enabling ASK1 activation and c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) signaling to promote apoptosis, senescence, and immune surveillance. In HCC, transcriptional repression, epigenetic silencing, and post-transcriptional regulation downregulate TBP2 and ASK1, fostering tumor cell survival, metabolic adaptation, and immune evasion. Both proteins intersect with the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which induce pyroptosis and provides antitumor immunity. This review synthesizes current mechanistic insights into TBP2/ASK1 regulation, their integration with redox and inflammasome signaling, and modulation by natural compounds such as curcumin, piperine and other natural compounds. We also examine therapeutic approaches including gene therapy, epigenetic reactivation, and redox-modulating agents. Translational challenges include context-dependent effects, biomarker limitations, and delivery specificity. Refining strategies to achieve precise, transient TBP2/ASK1 activation may unlock their tumor-suppressive potential while minimizing inflammatory risk, offering a novel avenue for HCC treatment.