Modified Tabusen-2, a Natural Multi-Herb Bioactive Formula with Antioxidant Potential, Ameliorates Kidney–Bone Axis Disorders in Rats via the STAT3/TP53 Axis and Steroid Hormone Biosynthesis

Background/Objectives: Postmenopausal osteoporosis (PMOP) and kidney-yang deficiency (KYD) are major kidney–bone axis disorders with a growing public health burden, yet current therapies are largely single-target and fail to address the coordinated dysfunction of the renal and skeletal systems. Modified Tabusen-2 (MT-2), a multi-herb Mongolian formula whose constituent herbs contain natural bioactive compounds with reported antioxidant and anti-inflammatory activities, reportedly improves both conditions; however, the shared molecular mechanism underlying its dual efficacy remains undefined, hindering its standardization and clinical translation. Methods: We integrated untargeted metabolomics, network pharmacology, targeted LC-MS/MS-based steroid hormone quantification, and qRT-PCR in rat models of hydrocortisone-induced KYD and ovariectomy-induced PMOP treated with MT-2 at high, medium, or low doses for 8 weeks. Results: MT-2 significantly alleviated pathological phenotypes and normalized serum biomarkers in both models. Network pharmacology and metabolomics converged on steroid hormone biosynthesis as the shared core pathway, and targeted quantification confirmed that seven serum steroid hormones were significantly dysregulated (p < 0.05) and effectively reversed by MT-2. qRT-PCR further showed that STAT3 and TP53, transcriptional hubs responsive to oxidative stress and inflammatory signaling, were significantly upregulated in disease groups (p < 0.05) and downregulated after MT-2 treatment. Conclusions: These findings provide molecular evidence supporting the “kidney governing bones” theory and suggest that MT-2 acts through coordinated regulation of steroid hormone biosynthesis and the STAT3/TP53 axis, supporting MT-2 as a multi-target natural bioactive candidate for kidney–bone axis disorders.