Orlistat Suppresses Small Intestinal Neuroendocrine Tumor Growth Through ATF3-Associated Stress and Ferroptosis-Related Responses—In Vitro and Cell Line Xenograft Evidence
- 1Department of Neuroendocrine Tumor, The First Affiliated Hospital with Nanjing Medical University, Neuroendocrine Tumor Diagnosis and Treatment Center of Jiangsu Province, Institute of Neuroendocrine Tumor of Nanjing Medical University, Nanjing 210029, China
Abstract
Background/Objectives: The incidence of small intestinal neuroendocrine tumors (SI-NETs) has increased in recent years, while effective therapeutic options remain limited. This study aimed to investigate the antitumor effects of orlistat on SI-NETs and elucidate the underlying mechanisms. Methods: The effects of orlistat were evaluated using STC-1 cells, patient-derived primary SI-NET cells, and xenograft models. Functional assays, RNA sequencing, lipidomic profiling, ATAC sequencing, and molecular analyses were performed to assess tumor-related phenotypes and investigate the underlying mechanisms. Results: Orlistat inhibited cell proliferation, migration, and invasion, induced G1-phase arrest and apoptosis, and suppressed tumor growth in vivo. Mechanistically, orlistat triggered endoplasmic reticulum stress, inhibited PI3K/AKT/mTOR signaling, and upregulated activating transcription factor 3 (ATF3). Lipidomic profiling revealed alterations in lipid metabolism. Increased reactive oxygen species and lipid peroxidation, together with changes in ferroptosis-related proteins, indicated the involvement of ferroptosis-associated pathways. ATF3 overexpression reproduced the antitumor and ferroptosis-associated effects of orlistat. Integrated ATAC-seq and RNA-seq analyses identified CHAC1 as a potential downstream effector of ATF3. Conversely, ATF3 knockdown reduced CHAC1 expression and attenuated the effects of orlistat both in vitro and in vivo. Conclusions: Orlistat suppresses SI-NET progression and is associated with changes in endoplasmic reticulum stress, ATF3 expression, and ferroptosis-related responses, with CHAC1 identified as a potential downstream effector of ATF3. These findings support further investigation of orlistat as a potential therapeutic strategy for SI-NETs.
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BibTeX
@article{zeng2026orlistat,
title = {{Orlistat Suppresses Small Intestinal Neuroendocrine Tumor Growth Through ATF3-Associated Stress and Ferroptosis-Related Responses—In Vitro and Cell Line Xenograft Evidence}},
author = {Xiangrui Zeng and Sixu Chen and Qin Long and Xu Han and Weilong Li and Jierong Ge and Yi Ding and Yixuan Ding and Mujie Ye and Qiyun Tang},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18203294},
url = {https://www.mdpi.com/2072-6694/18/20/3294},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Orlistat Suppresses Small Intestinal Neuroendocrine Tumor Growth Through ATF3-Associated Stress and Ferroptosis-Related Responses—In Vitro and Cell Line Xenograft Evidence
AU - Xiangrui Zeng
AU - Sixu Chen
AU - Qin Long
AU - Xu Han
AU - Weilong Li
AU - Jierong Ge
AU - Yi Ding
AU - Yixuan Ding
AU - Mujie Ye
AU - Qiyun Tang
PY - 2026
DA - 2026/10/13
JO - Cancers
DO - 10.3390/cancers18203294
UR - https://www.mdpi.com/2072-6694/18/20/3294
AB - Background/Objectives: The incidence of small intestinal neuroendocrine tumors (SI-NETs) has increased in recent years, while effective therapeutic options remain limited. This study aimed to investigate the antitumor effects of orlistat on SI-NETs and elucidate the underlying mechanisms. Methods: The effects of orlistat were evaluated using STC-1 cells, patient-derived primary SI-NET cells, and xenograft models. Functional assays, RNA sequencing, lipidomic profiling, ATAC sequencing, and molecular analyses were performed to assess tumor-related phenotypes and investigate the underlying mechanisms. Results: Orlistat inhibited cell proliferation, migration, and invasion, induced G1-phase arrest and apoptosis, and suppressed tumor growth in vivo. Mechanistically, orlistat triggered endoplasmic reticulum stress, inhibited PI3K/AKT/mTOR signaling, and upregulated activating transcription factor 3 (ATF3). Lipidomic profiling revealed alterations in lipid metabolism. Increased reactive oxygen species and lipid peroxidation, together with changes in ferroptosis-related proteins, indicated the involvement of ferroptosis-associated pathways. ATF3 overexpression reproduced the antitumor and ferroptosis-associated effects of orlistat. Integrated ATAC-seq and RNA-seq analyses identified CHAC1 as a potential downstream effector of ATF3. Conversely, ATF3 knockdown reduced CHAC1 expression and attenuated the effects of orlistat both in vitro and in vivo. Conclusions: Orlistat suppresses SI-NET progression and is associated with changes in endoplasmic reticulum stress, ATF3 expression, and ferroptosis-related responses, with CHAC1 identified as a potential downstream effector of ATF3. These findings support further investigation of orlistat as a potential therapeutic strategy for SI-NETs.
SN - 2072-6694
ER -