Lactoferrin alleviates non-alcoholic steatohepatitis via remodeling gut microbiota to regulate serotonin-related pathways

  • J Adv Res. 2025 Nov 16:S2090-1232(25)00930-0. doi: 10.1016/j.jare.2025.11.034.
Li Ding  1 ,  Jia-Ying Xu  2 ,  Li-Li Zhang  1 ,  Yan Liu  1 ,  Kai-Tian Gu  1 ,  Yan-Zi Liang  1 ,  Khemayanto Hidayat  1 ,  Zhongxiao Wan  1 ,  Guo-Chong Chen  3 ,  Li-Qiang Qin  4
Affiliations
  • 1. School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
  • 2. State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
  • 3. School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, China.
  • 4. School of Public Health, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, China. Electronic address: [email protected].
PMID: 41253270 DOI: 10.1016/j.jare.2025.11.034
Abstract

Introduction: lactoferrin (LF), a multifunctional glycoprotein, has been implicated in the regulation of glucose and lipid metabolism.

Objectives and methods: This study employed in vivo and in vitro models to investigate the direct effects of LF on non-alcoholic steatohepatitis (NASH) and to elucidate its underlying mechanisms.

Results: LF intervention alleviated hepatic lipid metabolic disorders and liver injury in high-fat, high-cholesterol cholate-containing diet (HFCCD)-fed mice by mitigating oxidative stress, suppressing the inflammatory cGAS/STING pathway, and reducing M1 proinflammatory macrophage polarization. These effects were validated in free fatty acid (FFA)-treated HepG2 cells and AML12 cells. Furthermore, LF ameliorated HFCCD-induced gut microbiota dysbiosis and increased short-chain fatty acid levels. The critical role of gut microbiota in mediating the hepatoprotective effects of LF was confirmed through antibiotic-induced microbiome depletion and fecal microbiota transplantation. Mechanistically, LF modulated gut-liver serotonin signaling and promoted fatty acid β-oxidation through the HTR2A-PPARα-CPT-1A pathway, an effect abolished by the HTR2A agonist DOI. In a co-culture system, LF treatment of the Caco-2/HT29 monolayer alleviated lipid accumulation and regulated the HTR2A-PPARα-CPT-1A pathway in FFA-treated HepG2 cells.

Conclusions: These findings indicate that LF attenuates NASH by remodeling gut microbiota to modulate microbiota-derived serotonin signaling and enhance fatty acid oxidation.

Keywords
Gut microbiota; Lactoferrin; Non-alcoholic steatohepatitis; cGAS/STING; serotonin receptor 2A.
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