Hussain Md Sadique, Jakhmola Vikash, Goyal Kavita, Rekha Arcot, Sultana Ayesha, Ali Haider, Gupta Gaurav
Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehra Dun 248007, Uttarākhand, India.
Department of Biotechnology, Graphic Era (Deemed to Be University), Dehra Dun 248002, Uttarākhand, India.
World J Gastroenterol. 2025 Jun 7;31(21):106530. doi: 10.3748/wjg.v31.i21.106530.
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.
在结直肠癌（CRC）中，奥沙利铂耐药仍然是一个重大的临床挑战，这凸显了迫切需要确定新的分子靶点用于治疗干预。牛等人最近的研究结果阐明了NAD⁺/SIRT1轴在通过代谢重编程介导奥沙利铂耐药中的作用。他们的研究表明，奥沙利铂诱导的DNA损伤激活PARP，导致NAD⁺耗竭以及随后SIRT1的下调。SIRT1水平的这种降低增强了糖酵解，PKM2和LDHA表达增加证明了这一点，从而赋予耐药CRC细胞代谢优势。相反，SIRT1表达的恢复逆转耐药，而糖酵解的药理学抑制有效地使细胞对奥沙利铂敏感。这些发现强调了靶向NAD⁺/SIRT1途径作为CRC代谢弱点的治疗潜力。未来的研究应调查将SIRT1激动剂和糖酵解抑制剂与奥沙利铂联合使用以克服耐药性并改善患者预后的临床可行性。
