Upregulation of SIRT6 enhances autophagy-dependent ferroptosis of colorectal cancer cells through inactivating the mTOR/STAT3 signaling pathway
Year: 2025
Type: article
Abstract: Accumulating evidence highlights the critical roles of autophagy-dependent ferroptosis mediators in colorectal cancer (CRC) pathogenesis. To elucidate SIRT6's tumor-suppressive role, HT29 cells stably overexpressing SIRT6 (Oe-SIRT6) were generated via plasmid transfection. Functional assays were performed to evaluate autophagy and ferroptosis. Rescue experiments using the autophagy inhibitor 3-MA or the mTOR agonist MHY1485 were conducted. Quantitative analyses revealed marked downregulation of SIRT6 expression in CRC cell lines (SW620, SW480, and HT29) compared to normal colon epithelial cells. SIRT6 overexpression induced autophagy and activated ferroptosis. The autophagy inhibitor 3-MA blocked SIRT6-driven ferroptosis, which confirmed its dependency on autophagy. Moreover, SIRT6 was found to inactivate mTOR/STAT3 signaling, whereas the mTOR agonist MHY1485 reversed SIRT6 overexpression on autophagy-dependent ferroptosis of CRC cells. Our findings establish SIRT6 as a dual-phase regulator of CRC cell death, suppressing mTOR/STAT3 signaling to orchestrate autophagy-dependent ferroptosis.
Source: Neoplasma
Authors: Yang Wang, Hong Xu, Yanbing Shen, Lei Liu, Xin Liu
Institution: Shanghai Jiao Tong University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416200290