2. Academic Validation
  3. PLIN5 deficiency ameliorates metabolic dysfunction‑associated fatty liver disease by inhibiting ferroptosis

PLIN5 deficiency ameliorates metabolic dysfunction‑associated fatty liver disease by inhibiting ferroptosis

  • Mol Med Rep. 2026 Jan;33(1):4. doi: 10.3892/mmr.2025.13714.
Ya Li 1,  Xiaohan Wang 2,  Xuecui Yin 3,  Xiaohui Zhu 2,  Weiqi Cui 4,  Lin Dong 2,  Yu Xia 2,  Ying Wang 5,  Liu Liu 2,  Pengyuan Zheng 6,  Youcai Tang 1
Affiliations

Affiliations

  • 1 Henan Joint International Research Laboratory of Chronic Liver Injury and Henan Provincial Outstanding Overseas Scientists Chronic Liver Injury Workshop, Henan Key Laboratory of Rehabilitation Medicine, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
  • 2 Department of Pediatrics, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
  • 3 Henan Key Laboratory of Helicobacter pylori, Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
  • 4 Department of Pharmacy, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
  • 5 Department of Blood Transfusion, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
  • 6 Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
PMID: 41104863 DOI: 10.3892/mmr.2025.13714
Abstract

Metabolic‑associated fatty liver disease (MAFLD) is widely recognized as the most common type of chronic liver disease. As a member of the perilipin (PLIN) family, PLIN5 serves an important role in the regulation of lipid metabolism. Ferroptosis is a form of iron‑dependent non‑apoptotic cell death characterized by lipid peroxidation. Notably, knockout of PLIN5 can attenuate high‑fat diet (HFD)‑induced MAFLD; however, the specific underlying mechanism remains unclear. The present study induced PLIN5 overexpression by transfecting AML12 cells with a pcDNA3.1‑PLIN5 plasmid, and PLIN5 knockdown was achieved using short hairpin RNA‑mediated interference. Subsequently, intracellular ferrous iron (Fe2+) levels were assessed via immunofluorescence staining. Furthermore, a MAFLD model was established in C57BL/6J mice by feeding them a HFD. To establish an in vitro model of hepatic steatosis, AML12 hepatocytes were treated with palmitic acid and oleic acid to induce intracellular lipid accumulation. To further explore the effects of PLIN5 on Ferroptosis, liver single‑cell Sequencing was conducted and cellular experiments were performed to assess changes in redox and ferroptosis‑related proteins. The current study investigated the effects of PLIN5 on MAFLD in animal and cellular experiments, including the changes in lipid accumulation, redox and ferroptosis‑related markers. The results revealed that genetic knockdown of PLIN5 significantly attenuated lipid accumulation and intracellular Fe2+ levels in AML12 hepatocytes, whereas PLIN5 overexpression markedly exacerbated these parameters. In addition, PLIN5 deficiency substantially reduced malondialdehyde content while enhancing glutathione levels, indicating attenuated oxidative stress. The results of the in vivo studies demonstrated that PLIN5 knockout effectively ameliorated MAFLD progression in mice by suppressing Ferroptosis. In conclusion, PLIN5 knockout may delay the progression of MAFLD in mice via Ferroptosis inhibition. Therefore, targeting PLIN5 could offer a novel therapeutic strategy to address MAFLD by modulating lipid metabolism and Ferroptosis pathways.

Keywords

activating transcription factor 3; ferroptosis; lipid accumulation; metabolic‑associated fatty liver disease; perilipin 5.

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