Targeting aldose reductase in pulmonary fibrosis: Blocking de novo fatty acid synthesis halts pro-fibrotic M2 polarization

Aldose Reductase (AR) inhibitors ameliorate renal and cardiac fibrosis associated with diabetes. However, the role of AR in idiopathic pulmonary fibrosis (IPF) remains unclear. Here, we observed elevated AR expression and activity in the serum of patients with IPF and in the lungs of mice and rats with bleomycin - induced pulmonary fibrosis. Spearman correlation analysis further showed that AR enzyme activity was positively correlated with lung fibrosis scores. Overexpression of AR led to Collagen deposition and increased levels of M2-type macrophages. Conversely, AR knockdown mitigated bleomycin-induced pulmonary fibrosis in mice and significantly reduced lung levels of M2-type macrophages. In an interleukin-4 (IL-4)-induced macrophage M2 polarization model, transcriptome Sequencing combined with KEGG pathway enrichment analysis indicated that lipid metabolism is a core pathway in M2 polarization. AR knockdown could inhibit M2 polarization and reduce the expression of fatty acid de novo synthesis pathway key Enzymes fatty acid synthase (FASN) and Acetyl-CoA Carboxylase alpha (ACC1). Prediction of transcription factors for FASN and ACC1 using the CHEA3 database revealed that MYC is a potential factor regulating the transcription of FASN and ACC1. Western blot (WB) results showed that AR could activate the extracellular regulated protein kinases (ERK)- myelocytomatosis oncogene (MYC) signaling pathway, and the MYC inhibitor MYCMI-6 could inhibit the transcription of FASN and ACC1. In addition, Epalrestat, an inhibitor of AR, significantly ameliorated pulmonary fibrosis in mice. Our findings indicate that AR plays a crucial role in pulmonary fibrosis by activating ERK-MYC signaling, promoting the expression of FASN and ACC1, enhancing fatty acid synthesis, and inducing macrophage M2 polarization. Notably, Epalrestat-an Aldose Reductase Inhibitor approved by the Food and Drug Administration (FDA) for the treatment of diabetic neuropathy-exhibits potent antifibrotic effects in preclinical models, which supports its immediate clinical applicability for the repurposing of IPF treatment.

Aldose reductase; Epalrestat; Fatty acid synthase; Macrophage M2 polarization; Pulmonary fibrosis.