Work

NXPH4 coordinates DNA repair and macrophage polarization to promote chemoresistance in colorectal cancer

Year: 2026

Type: preprint

Abstract: Chemoresistance remains a major barrier to effective treatment of advanced colorectal cancer (CRC). Neurexophilin-4 (NXPH4), a secreted glycoprotein linked to tumor progression, has not been mechanistically defined in CRC chemoresistance. We integrated transcriptomic datasets from chemotherapy-sensitive and -resistant CRC tissues and evaluated NXPH4 expression in clinical samples and CRC models. In a plasma cohort of 190 patients with metastatic CRC, higher NXPH4 levels were associated with chemotherapy non-response and shorter overall and progression-free survival, with moderate discriminatory performance for treatment response (AUC = 0.773). Mechanistically, nuclear NXPH4 interacted with hnRNPC and was associated with increased hnRNPC protein stability, MCM2-7 expression, and resistance to chemotherapy-induced DNA damage. Secreted NXPH4 altered macrophage cholesterol homeostasis by suppressing ABCA1 and ABCG1 and was associated with a STAT6-PPARγ-linked M2-like phenotype. Conditioned medium from NXPH4-treated macrophages reduced CRC cell sensitivity to oxaliplatin and 5-fluorouracil. Upstream, ZNF263 promoted NXPH4 transcription through promoter binding. Collectively, these findings identify NXPH4 as a candidate biomarker and mechanistic contributor to CRC chemoresistance and suggest that NXPH4 links tumor-intrinsic DNA damage responses with macrophage immunometabolic remodeling.

Source: Research Square

DOI: 10.21203/rs.3.rs-10604637/v1