Targeted Inhibition of Aldose Reductase by Isoliquiritigenin Suppresses Fatty Acid Synthesis to Inhibit Macrophage M2 Polarization and Alleviate Pulmonary Fibrosis

Isoliquiritigenin (ISL), a flavonoid derived from licorice root, has received widespread attention due to its multifaceted therapeutic effects. This study demonstrates that ISL mitigates bleomycin-induced pulmonary fibrosis and macrophage M2 polarization. Using a combination of transcriptomic analyses, we found that ISL downregulated ERK signaling and genes associated with fatty acid synthesis (FAS). Aldose reductase (AR) was found to have a reduced activity and expression in ISL-treated mice. AR knockdown and AR inhibitor epalrestat suppressed the ERK-MYC signaling pathway, FAS, and macrophage M2 polarization. Conversely, the overexpression of AR negated these effects. Collectively, these findings suggest that ISL inhibits FAS, thereby suppressing macrophage M2 polarization and improving pulmonary fibrosis through modulation of the ERK signaling pathway by targeting AR. ISL may be a potentially effective medicine and food additive for the treatment of pulmonary fibrosis.