AIEgen Targets the STAT3‒SUCLG2 Axis to Regulate Metabolism for Colorectal Cancer Theranostics

Abstract

The integration of precise diagnosis with mechanism-based therapy remains a pivotal challenge in colorectal oncology. Here, building on the triphenylamine (TPA) core, we employed a donor‒acceptor (D‒A) molecular design strategy by integrating a pyridinium acceptor to engineer TPA-FB, a derivative exhibiting aggregation-induced emission (AIE) characteristic. Both in vitro and in vivo experiments demonstrated that TPA-FB functioned as an effective theranostic agent against colorectal cancer (CRC). Prompted by its molecular structure and notable biological activity, we sought to identify its specific cellular target. We discovered that TPA-FB directly binds to and inhibits the phosphorylation of STAT3, leading to downregulation of SUCLG2. Suppression of SUCLG2 thereby disrupts the tricarboxylic acid (TCA) cycle, reducing succinate and its downstream metabolites, which also disrupts critical protein succinylation modifications. By employing our designed AIEgen to selectively disrupt the STAT3‒SUCLG2 axis, we offer a transformative perspective for the development of CRC therapeutics.

Keywords

aggregation-induced emission / colorectal cancer / mitochondrial metabolic dysfunction / STAT3 / SUCLG2

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RIGHTS & PERMISSIONS

2026 The Author(s). Aggregate published by SCUT, AIEI, and John Wiley & Sons Australia, Ltd.