Withania somnifera Root Extract Ameliorates PTU-Induced Hypothyroidism by Regulating Hormone Levels and Gene...

Hypothyroidism is a prevalent endocrine disorder characterized by the inadequate production of thyroid hormones (T3 and T4), leading to various physiological dysfunctions. Current treatments often involve synthetic hormone replacement, which is limited by some adverse effects. This study investigated the therapeutic efficacy of a methanolic extract of Withania somnifera root (MEWS) in propylthiouracil (PTU)-induced hypothyroid rats. Forty rats were divided into five groups (n = 8): (1) negative control (NC), receiving no treatment; (2) positive control (PC), administered 0.05% w/v PTU to induce hypothyroidism; (3) W. somnifera control (WSC), treated with 500 mg/kg/day MEWS alone; (4) W. somnifera treatment (WST-500), receiving 500 mg/kg/day MEWS alongside PTU; and (5) combination therapy (CT-500), treated with both 500 mg/kg/day MEWS and 0.05% w/v PTU. Serum hormones (TSH, T3, T4) were measured by ELISA, thyroid histopathology was analyzed, and thyroperoxidase (TPO) and thyroglobulin (TG) gene expression were quantified by qPCR. Molecular docking and ADMET profiling were employed to identify bioactive phytochemicals that target the thyroid-stimulating hormone receptor (TSHR) and Type 2 iodothyronine deiodinase (D2). PTU induction significantly increased thyroid weight (175.8%), TSH levels (4.45-fold), and TPO/TG expression (4.28 and 3.10-fold), while reducing T3 and T4 (82% and 75%; all p < 0.05). MEWS treatment (WST-500) significantly reversed these effects, reducing thyroid weight (55.8%), TSH (74.2%), and TPO/TG expression, while restoring T3 and T4 levels to near-normal (p < 0.05). Histopathology revealed reduced fibrosis and improved follicular architecture. A computational study identified phytochemicals with strong binding affinities for TSHR and D2 and favorable ADMET properties. These findings suggest that MEWS may ameliorate hypothyroidism by regulating hormone levels, gene expression, and thyroid morphology, indicating its potential as an adjunct or alternative to conventional hormone replacement therapies for hypothyroidism.