Triptolide enhances oxaliplatin sensitivity by suppressing the JAK2/STAT3 pathway in cancer cells

Liver cancer and lung cancer are major causes of cancer-related deaths worldwide. Oxaliplatin is a first-line chemotherapeutic agent, but its efficacy is often limited by acquired resistance.

This study investigated whether triptolide (TPL), a bioactive compound derived from a traditional Chinese medicinal herb, enhances the sensitivity of cancer cells to oxaliplatin and explored the underlying molecular mechanism.

Human liver cancer (Huh-7) and lung cancer (A549) cell lines were used as experimental models. Western blotting was performed to assess the effects of oxaliplatin on the signal transducer and activator of transcription 3 (STAT3) pathway. Cells were treated with oxaliplatin alone, a STAT3 inhibitor, STAT3 small interfering RNA, TPL alone, or their combinations, both in vitro and in vivo. Molecular docking, drug affinity responsive target stability, cellular thermal shift assay, and surface plasmon resonance were employed to identify and validate the direct binding between TPL and STAT3. Immunoprecipitation was used to examine STAT3 ubiquitination levels.

Oxaliplatin treatment activated the STAT3 pathway in cancer cells. Inhibition of STAT3 either by a pharmacological inhibitor or by small interfering RNA significantly enhanced cellular sensitivity to oxaliplatin. RNA sequencing analysis revealed that TPL modulated STAT3-related pathways. Combination of TPL and oxaliplatin produced synergistic antitumor effects in both cell-based and animal models. Mechanistically, TPL directly bound to STAT3 at the Lys244 and Lys318 residues, promoting its ubiquitination and subsequent degradation.

TPL acts as a novel small-molecule STAT3 inhibitor that promotes STATA3 ubiquitination-mediated degration, representing a promising candidate to sensitize tumors to oxaliplatin-based therapy.