Fangchinoline eliminates intracellular Salmonella by enhancing lysosomal function via the AMPK-mTORC1-TFEB axis

Mengping He; Huihui Wu; Tianqi Xu; Yurong Zhao; Zhiqiang Wang; Yuan Liu

doi:10.1016/j.jare.2025.01.015

Fangchinoline eliminates intracellular Salmonella by enhancing lysosomal function via the AMPK-mTORC1-TFEB axis

J Adv Res. 2025 Jan 7:S2090-1232(25)00034-7. doi: 10.1016/j.jare.2025.01.015. Online ahead of print.

Authors

Mengping He¹, Huihui Wu¹, Tianqi Xu¹, Yurong Zhao¹, Zhiqiang Wang², Yuan Liu³

Affiliations

¹ Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.
² Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, China. Electronic address: [email protected].
³ Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, China; Institute of Comparative Medicine, Yangzhou University, Yangzhou, China. Electronic address: [email protected].

PMID: 39788287
DOI: 10.1016/j.jare.2025.01.015

Abstract

Introduction: Salmonella, a foodborne zoonotic pathogen, is a significant cause of morbidity and mortality in animals and humans globally. With the prevalence of multidrug-resistant strains, Salmonellosis has become a formidable challenge. Host-directed therapy (HDT) has recently emerged as a promising anti-infective approach for treating intracellular bacterial infections.

Objectives: Plant-derived natural products, owing to their structural and functional diversity, are increasingly being explored and utilized as encouraging candidates for HDT compounds. This study aims to identify and screen natural compounds with potential as HDT for the treatment of intracellular Salmonella infections.

Methods: A cell-based screening approach was deployed to identify natural compounds capable of mitigating the intracellular replication of S. enterica. Safety and efficacy of the candidate compounds were evaluated using multiple animal models. RNA sequencing, ELISA, and immunoblotting analyses were conducted to elucidate the underlying mechanisms of action.

Results: Our results reveal that fangchinoline (FAN) effectively reduces S. enterica survival both in vitro and in vivo. Meanwhile, FAN also displays anti-infective activity against other intracellular pathogens, including multidrug-resistant isolates. A 14-day safety evaluation in mice showed no significant toxic or adverse effects from FAN administration. RNA sequencing analysis reveals an upregulation of lysosome pathways in S. enterica-infected cells treated with FAN. Mechanistic studies indicate that FAN increases acid lysosomal quantities and fosters autophagic response in Salmonella-infected cells the AMPK-mTORC1-TFEB axis. In addition, FAN alleviates the inflammatory response in Salmonella-infected cells by inactivating the NF-κB pathway.

Conclusion: Our findings suggest that FAN represents a lead HDT compound for tackling recalcitrant infections caused by intracellular bacterial pathogens.

Keywords: Fangchinoline; Host-directed therapy; Inflammatory; Lysosome; Salmonella.