P65‐Driven MIR4435‐2HG Enhances Prognostic Value and Mediates Oxaliplatin Resistance via the miR‐378G/ABCB9 Axis in Colorectal Cancer

ABSTRACT Long non‐coding RNA MIR4435‐2HG has emerged as a pivotal oncogenic factor across various cancers. However, its role in chemoresistance, particularly in colorectal cancer (CRC), remains unclear. This work demonstrates that MIR4435‐2HG is significantly overexpressed in CRC tissues, correlating with poor prognosis and resistance to oxaliplatin (L‐OHP) based chemotherapy. Mechanistically, MIR4435‐2HG binds to miR‐378g, leading to elevated ABCB9 levels, a crucial factor in drug resistance. Both in vitro and in vivo experiments indicate that the MIR4435‐2HG/miR‐378g/ABCB9 axis confers L‐OHP resistance in CRC cells by reducing DNA damage and enhancing cell survival. Additionally, P65, a component of the NF‐κB pathway, directly promotes MIR4435‐2HG transcription, triggering subsequent chemoresistance. Based on these results, MIR4435‐2HG is recognized as a reliable prognostic marker and serves as a target for therapeutic strategies, presenting new approaches to counteract L‐OHP resistance and enhance CRC patient outcomes.