Publication Name	World Journal of Gastroenterology
Manuscript ID	126038
Country	China

Category	Gastroenterology & Hepatology
Manuscript Type	Basic Study
Article Title	USP4-IRF1 positive feedback loop promotes malignant progression of KRAS-mutated pancreatic cancer by enhancing CHUK-mediated mTOR bypass activation
Manuscript Source	Unsolicited Manuscript
All Author List	Ji-Chuan Xu, Xue Wang, Hong-Chun Dai, Jing-Yu Li, Yu Nie, Fei-Qiang Xu, Zhong-Jun Wu and Wei Huang
Funding Agency and Grant Number	Funding Agency Grant Number the Science and Technology Bureau of Tongnan District, Chongqing TK-2022-5
Corresponding Author	Wei Huang, Department of Hepatobiliary Surgery, The First Hospital Affiliated to Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, Chongqing 400038, China. huangjlwei@163.com
Key Words	Ubiquitin-specific protease 4; Interferon regulatory factor 1; Feedback loop; Pancreatic ductal adenocarcinoma; KRAS mutation; Malignant progression
Core Tip	As the main pathological type of pancreatic cancer, more than 90% of pancreatic ductal adenocarcinoma (PDAC) patients possess KRAS mutation. Compared with KRAS wild-type patients, the survival prognosis of KRAS mutant PDAC patients is worse due to the continuous activation of KRAS and downstream tumor-promoting molecular signals. Moreover, drug resistance of KRAS inhibitor may occur even after marketing for clinical treatment, so it is necessary to find other new therapeutic targets. Here, upregulation of interferon regulatory factor 1 (IRF1) in KRAS-mutated PDAC indicates poor prognosis. Ubiquitin-specific protease 4 (USP4) is identified by DUBs-siRNA library, which interacts with and stabilizes IRF1 protein via K48 deubiquitylation manner. Additionally, USP4 accelerates the proliferation and migration of KRAS-mutated PDAC cells dependent on IRF1. Intriguingly, USP4-mediated nuclear localization and activation of IRF1 transcriptionally upregulates USP4 in return, thereby forming the USP4-IRF1 positive feedback loop in KRAS-mutated PDAC. More importantly, USP4-IRF1 positive feedback loop promotes mTOR bypass activation through upregulating CHUK without relying on AKT-mediated direct activation.
Citation	Xu JC, Wang X, Dai HC, Li JY, Nie Y, Xu FQ, Wu ZJ, Huang W. USP4-IRF1 positive feedback loop promotes malignant progression of KRAS-mutated pancreatic cancer by enhancing CHUK-mediated mTOR bypass activation. World J Gastroenterol 2026; In press

Received	2026-07-30 03:35
Peer-Review Started	2026-08-05 07:22
First Decision by Editorial Office Director
Return for Revision	2026-09-07 02:14
Revised	2026-09-16 11:19
Publication Fee Transferred
Second Decision by Editor	2026-11-10 03:17
Second Decision by Editor-in-Chief
Final Decision by Editorial Office Director	2026-11-10 10:18
Articles in Press	2026-11-10 10:18
Edit the Manuscript by Language Editor
Typeset the Manuscript

ISSN	1007-9327 (print) and 2219-2840 (online)
Open Access	This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See Permissions. Published by Baishideng Publishing Group Inc.
Copyright	©Author(s) (or their employer(s)) 2026. No commercial re-use. See Permissions. Published by Baishideng Publishing Group Inc.
Permissions	For details, please visit: http://www.wjgnet.com/bpg/gerinfo/207
Publisher	Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
Website	http://www.wjgnet.com