Isolinderalactone Suppresses the Progression of Cholangiocarcinoma by Modulating the CARMA1-BCL10-MALT1 Signalosome

Abstract Cholangiocarcinoma (CCA) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. While Isolinderalactone (ILL) has shown anticancer potential, its effects and underlying mechanisms in CCA remain unclear. This study investigated the anti-CCA activity of ILL and elucidated its molecular mechanisms. ILL significantly inhibited CCA cell viability, proliferation, migration, and invasion, while also inducing G0/G1 cell cycle arrest and promoting apoptosis. Transcriptomic and biochemical analyses revealed that ILL suppressed the NF-κB signaling pathway by inhibiting IκB phosphorylation and p65 activation. Mechanistically, ILL was found to directly bind to BCL10, a key adaptor protein. This interaction disrupted the formation of the CARMA1-BCL10-MALT1 (CBM) signalosome and consequently reduced BCL10 ubiquitination. Functional experiments confirmed this mechanism: BCL10 knockdown mimicked ILL's inhibitory effects, while a BCL10 mutation abolished them. Furthermore, activation of NF-κB with Diprovocim partially reversed ILL's suppressive effects. In a xenograft nude mouse model, ILL effectively reduced tumor growth without significant toxicity and suppressed NF-κB activation in tumor tissues. These findings demonstrate that Isolinderalactone suppresses CCA progression by modulating the CBM signalosome and BCL10 ubiquitination to regulate the NF-κB pathway, supporting its potential as a promising therapeutic candidate for CCA.