Protocatechuic acid promotes c-Myc-mediated cell proliferation by directly targeting TRAF2

Protocatechuic acid (PCA) is both a prominent gut microbiota-derived metabolite of anthocyanins and a naturally occurring phenolic acid presents in various edible plants. Although this compound has been reported to exert cytotoxic effects at millimolar concentrations in vitro, its plasma levels following dietary intake are limited to the non-toxic nano-to micromolar range. Here, we identify the adaptor protein TNF Receptor Associated Factor 2 (TRAF2) as a direct molecular target of this phenolic compound. By computational modeling and biophysical assays, including fluorescence spectroscopy and calorimetry, we demonstrate that PCA directly binds the TRAF domain of TRAF2, leading to decreased thermal stability and potential alteration of trimeric interfaces. By performing functional analyses in HAP1 leukemia cells, we provide evidence that PCA, at low micromolar concentrations, increases cell viability through a TRAF2-dependent mechanism. Mechanistically, PCA binding to TRAF2 inhibits JNK signaling while redirecting TRAF2 toward pro-survival signaling routes involving c-Myc. Collectively, these findings uncover TRAF2 as a novel molecular target of PCA and provide a mechanistic basis for its effects on cell viability.