Integrative Metabolomic, Network Pharmacology, and Experimental Evidence for Lepidium sativum Seed Extract as a Natural Modulator of Pulmonary Fibrosis via the ncNRFR/Let-7d Regulatory Pathway

<b>Background/Objectives</b>: Pulmonary fibrosis (PF) is a progressive interstitial lung disease with limited therapeutic options. <i>Lepidium sativum</i> (cress seeds) possess recognized antioxidant and anti-inflammatory properties, yet its potential antifibrotic activity has not been investigated. This study evaluated the phytochemical composition and antifibrotic efficacy of cress seed extract (CSE) and examined whether its effects are associated with modulation of the <i>ncNRFR/let-7d</i> pathway in methotrexate (Mtx)-induced PF. <b>Methods</b>: Comprehensive metabolite profiling was performed using GC-MS, HPLC, and UPLC-T-TOF-MS/MS. Antioxidant capacity and antiproliferative effects were assessed in vitro. Network pharmacology was used to identify CSE-related PF targets and regulatory pathways. In vivo, PF was induced in adult male Wistar rats by Mtx, followed by oral CSE administration (50-150 mg/kg). Biochemical markers of inflammation, oxidative stress, extracellular matrix deposition, EMT, and ncRNA expression (<i>ncNRFR</i> and <i>let-7d</i>) were quantified alongside histopathology and immunohistochemistry. <b>Results</b>: CSE contained diverse terpenes, phenolics, flavonoids, glucosinolates, and amino acid derivatives. It exhibited potent antioxidant activity and antiproliferative effects against A549 and Hep2 lung cancer cells. Network analysis identified 997 overlapping CSE-PF targets and highlighted IL6 and MMP1 as relevant <i>miR-let-7d</i>-associated nodes. In vivo, Mtx-induced marked fibrosis characterized by increased <i>ncNRFR</i>, reduced <i>let-7d</i>, elevated IL6, HMGB1, TGF-β, MMP1, collagen, and hydroxyproline, and reduced antioxidant enzyme activity. CSE treatment dose-dependently mitigated these alterations, improved histoarchitecture, and reduced collagen deposition. <b>Conclusions</b>: CSE showed antifibrotic, antioxidant, and anti-inflammatory activity in MTX-induced PF in rats and modulated the reciprocal expression patterns of <i>ncNRFR</i> and <i>let-7d</i>. These findings support CSE as a potential source of bioactive constituents for PF management and identify the putative <i>ncNRFR-let-7d</i> regulatory relationship as a novel pathway in fibrotic lung disease, warranting further mechanistic investigation.