Estrogen upregulates NR4A1 to counter TGF beta induced pulmonary fibrosis therapeutic insights for IPF

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options and a poor prognosis. Here, we identify the nuclear receptor NR4A1 as a pivotal mediator of estrogen's antifibrotic effects through its regulation of TGF-β signaling. Clinical analysis revealed increased expression of NR4A1 and estrogen receptor α (ERα) in IPF lung tissues, with NR4A1 phosphorylation correlating with disease progression. Mechanistic investigations demonstrated that sustained TGF-β signaling induces NR4A1 phosphorylation, impairing its negative feedback regulation of fibrosis. Estrogen, acting via ERα, restored NR4A1 activity by suppressing phosphorylation, thereby reducing fibrosis both <i>in vitro</i> and <i>in vivo</i>. Overexpression of NR4A1 or inhibition of its phosphorylation attenuated fibrotic responses, whereas NR4A1 deficiency abrogated estrogen's protective effects. These findings elucidate a previously unrecognized mechanism of estrogen-mediated antifibrotic activity and highlight NR4A1 as a promising therapeutic target for IPF.