Targeting LIG1 to overcome oxaliplatin resistance by inducing PANoptosis in colorectal cancer.

Oxaliplatin-based chemotherapy is the first-line treatment for colorectal cancer (CRC) patients, but its clinical efficacy is hindered by therapeutic resistance. Here, we demonstrate that DNA ligase 1 (LIG1) is highly expressed in CRC and impairs chemosensitivity, highlighting LIG1 as a promising therapeutic target. However, the mechanism by which targeting LIG1 enhances chemosensitivity to oxaliplatin remains incompletely defined, and no highly selective LIG1 inhibitors have been identified to date. In this study, a library of 1220 natural compounds was screened to identify LIG1 inhibitors. As a result, gambogenic acid (GNA) was identified as a selective LIG1-binding candidate followed by cell-based cytotoxicity assays. Subsequently, we show that GNA treatment markedly enhances oxaliplatin chemosensitivity in CRC cells, drug-tolerant persister (DTP) cells, organoids, and in vivo tumor models. Moreover, the combination of GNA with FOLFOX (oxaliplatin + 5-fluorouracil + calcium levofolinate) also improves tumor responsiveness to anti-PD-1 immunotherapy. Mechanistically, GNA combined with oxaliplatin triggers ZBP1-dependent PANoptosis. Further investigations unveil that GNA suppresses DNA repair by targeting LIG1, thereby enhancing the DNA damage response and ultimately promoting PANoptosis and immunogenic cell death (ICD), which establishes a mechanistic link between LIG1 inhibition and PANoptosis induction. Overall, our findings suggest that LIG1 can be explored as a key target for oxaliplatin chemosensitivity in CRC and targeting LIG1 by GNA may be a promising therapeutic strategy for augmenting the sensitivity of CRC cells to oxaliplatin and anti-PD-1 treatment.