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World J Gastroenterol. Jun 7, 2025; 31(21): 106530
Published online Jun 7, 2025. doi: 10.3748/wjg.v31.i21.106530
Targeting the NAD+/SIRT1 axis: A metabolic strategy to overcome oxaliplatin resistance in colorectal cancer
Md Sadique Hussain, Vikash Jakhmola, Kavita Goyal, Arcot Rekha, Ayesha Sultana, Haider Ali, Gaurav Gupta
Md Sadique Hussain, Vikash Jakhmola, Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehra Dun 248007, Uttarākhand, India
Kavita Goyal, Department of Biotechnology, Graphic Era (Deemed to Be University), Dehra Dun 248002, Uttarākhand, India
Arcot Rekha, Department of General Surgery, Dr. D.Y. Patil Medical College, Hospital and Research Centre, Pune 411018, Mahārāshtra, India
Ayesha Sultana, Department of Pharmaceutics, Sree Dattha Institute of Pharmacy, Hyderabad 501510, Telangāna, India
Haider Ali, Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 602105, Tamil Nādu, India
Gaurav Gupta, Centre for Research Impact & Outcome-Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India
Gaurav Gupta, Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman 13306, United Arab Emirates
Co-corresponding authors: Md Sadique Hussain and Gaurav Gupta.
Author contributions: Hussain MS and Gupta G contribute equally to this study as co-corresponding authors; Hussain MS was responsible for conceptualization, data curation, writing – original draft; Jakhmola V was responsible for investigation, writing – original draft; Goyal K was responsible for formal analysis, investigation; Rekha A was responsible for data curation, writing – original draft; Sultana A was responsible for conceptualization, methodology, writing – original draft; Ali H was responsible for formal analysis, validation; Gupta G was responsible for conceptualization, supervision, writing – review & editing.
Conflict-of-interest statement: All the authors have no conflict of interest related to the manuscript.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Md Sadique Hussain, PhD, Assistant Professor, Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Prem Nagar, Dehra Dun 248007, Uttarākhand, India. sadiquehussain007@gmail.com
Received: February 28, 2025
Revised: March 21, 2025
Accepted: April 16, 2025
Published online: June 7, 2025
Processing time: 98 Days and 7.5 Hours
Abstract

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 et al 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.

Keywords: SIRT1; Glycolysis; Drug resistance; Colorectal cancer; Chemotherapy

Core Tip: Oxaliplatin resistance remains a major clinical challenge in colorectal cancer (CRC). This study underscores the critical role of the NAD+/SIRT1 axis in driving metabolic reprogramming that facilitates resistance. Oxaliplatin-induced DNA damage activates PARP, leading to NAD+ depletion and subsequent downregulation of SIRT1. This reduction in SIRT1 expression enhances glycolysis, marked by upregulation of PKM2 and LDHA. Notable, restoration of SIRT1 reverses resistance, while glycolysis inhibition sensitizes CRC cells to oxaliplatin. These findings suggest that targeting the NAD+/SIRT1 pathway, through SIRT1 agonists and glycolysis inhibitors, offers a promising metabolic strategy to overcome chemoresistance and improve therapeutic outcomes in CRC patients.