PDLIM4 increases sphingolipid accumulation to promote cancer stem cell characteristics and chemotherapy resistance in colorectal cancer

The prognosis for advanced colorectal cancer (CRC) remains poor, and 5-fluorouracil (5-FU)-based chemotherapy is the primary treatment option. Understanding the mechanisms that limit the effectiveness of this therapy is therefore clinically important. However, the molecular drivers of acquired chemotherapy resistance in advanced CRC are not fully understood. Here we show that expression of PDZ-LIM domain-containing protein 4 (PDLIM4) is significantly upregulated following neoadjuvant chemotherapy in patients with advanced CRC, and that its expression level is closely associated with patient prognosis. PDLIM4 promotes acquired resistance to 5-FU by enhancing the stemness, anti-apoptotic capacity, and drug efflux of colorectal cancer stem cells. Mechanistically, PDLIM4 facilitates the accumulation of sphingolipids, particularly sphingomyelin, and regulates the PI3K/Akt signaling pathway. These findings identify PDLIM4 as a potential biomarker and therapeutic target for overcoming chemoresistance in advanced colorectal cancer, opening new avenues for future treatment strategies. Single-cell sequencing of advanced colorectal cancer reveals PDLIM4 upregulation after neoadjuvant chemotherapy, promoting 5-FU resistance by enhancing cancer stem cell stemness, anti-apoptosis, and drug efflux via sphingolipid accumulation and PI3K/Akt signaling.