Erchen Decoction Alleviates MAFLD by Regulating MFN2-mediated Endoplasmic Reticulum Stress

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent chronic liver condition lacking approved pharmacological therapies. Erchen Decoction (EC), a classic traditional Chinese medicine prescription, possesses the therapeutic effects of strengthening the spleen, resolving dampness, and eliminating phlegm. This study aims to investigate the therapeutic potential and underlying mechanisms of EC against MAFLD.

The anti-MAFLD efficacy of EC was evaluated using a high-fat diet (HFD)-induced rat model and palmitic acid-stimulated AML12 cells. Therapeutic outcomes were assessed by measuring body and liver weights, serum biochemical parameters, and hepatic histological changes. The regulatory effects of EC on endoplasmic reticulum stress (ERS) were analyzed via immunohistochemistry, Western blotting, and qRT-PCR. Furthermore, MFN2 knockdown was employed to verify whether EC alleviates MAFLD via the MFN2 pathway.

EC administration significantly ameliorated hepatic steatosis and injury in both in vivo and in vitro models. Mechanistically, EC upregulated the expressions of MFN2 and its splicing variant ERMIT2, thereby suppressing the activation of ERS-related signaling molecules, including PERK, eIF2α, and ATF4. Consequently, EC mitigated ERS, reduced lipid accumulation, and hindered MAFLD progression.

The findings highlight the critical role of the MFN2/ERMIT2 signaling axis in regulating endoplasmic reticulum stress during MAFLD pathogenesis. By restoring this organelle tethering complex, EC effectively buffers calcium handling, maintains global ER homeostasis, and mitigates lipotoxic hepatocyte injury, offering a novel pharmacological rationale for its traditional application in metabolic disorders.

EC exerts significant protective effects against MAFLD by upregulating the MFN2/ERMIT2 axis and suppressing the PERK, eIF2α, and ATF4 ERS pathway. This regulation suggests a restorative effect on calcium handling, maintains ER homeostasis, and reduces hepatocyte injury, highlighting EC as a promising therapeutic candidate for MAFLD.