Oxaliplatin resistance remains a significant clinical challenge in colorectal cancer (CRC), highlighting the urgent need to identify novel molecular targets for therapeutic intervention. Recent findings by Niu have elucidated the role of the NAD+/SIRT1 axis in mediating oxaliplatin resistance through metabolic reprogramming. Their study demonstrated that oxaliplatin-induced DNA damage activates PARP, resulting in NAD+ depletion and subsequent downregulation of SIRT1. This reduction in SIRT1 levels enhances glycolysis, as evidenced by increased expression of PKM2 and LDHA, thereby conferring a metabolic advantage to resistant CRC cells. Conversely, restoration of SIRT1 expression reverses resistance, while pharmacological inhibition of glycolysis effectively sensitizes cells to oxaliplatin. These findings underscore the therapeutic potential of targeting the NAD+/SIRT1 pathway as a metabolic vulnerability in CRC. Future studies should investigate the clinical feasibility of combining SIRT1 agonists and glycolysis inhibitors with oxaliplatin to overcome drug resistance and improve patient outcomes.