NLRC3 suppresses hepatocarcinogenesis by disrupting the HSP90-mediated TRAF6/MYC signalling activation.

NLRC3 serves as a critical negative regulator of inflammatory signalling pathways and is implicated in the pathogenesis of multiple disorders, including inflammatory diseases and malignancies. However, the specific functions and underlying mechanisms of NLRC3 in hepatocellular carcinoma (HCC) development remain largely elusive. Here, we report that the expression of NLRC3 was downregulated in HCC tissues and was associated with poor prognosis. Mice deficient in NLRC3 were hypersusceptible to chemically induced hepatocarcinogenesis, and NLRC3 exerted a tumour-suppressive function during HCC development by inhibiting the TRAF6/MYC/NF-κB signalling cascade. Mechanistically, the NLRC3-HSP90 interaction competitively inhibited the binding of the HSP90 chaperone to TRAF6/MYC and impaired the K63-linked ubiquitination and stabilization of the TRAF6/MYC proteins. In the absence of NLRC3, TRAF6 and MYC reciprocally regulated the expression of the other and triggered a TRAF6-MYC positive feedback loop that accelerated the progression of HCC. Our study reveals a novel functional link between NLRC3 and MYC signalling and indicates that HSP90 is a potential target for hindering the progression of NLRC3-deficient HCC.