Heart failure (HF) represents a major challenge in public health. Baicalin constitutes a primary active component derived from the traditional Chinese herb Huang Qin (Scutellaria baicalensis), commonly employed in managing patients experiencing chest pain or cardiac-related unease. Nevertheless, the precise mechanisms responsible for baicalin’s protective actions on the heart remain incompletely elucidated. Experimental models of heart failure were developed using isoprenaline administration or transverse aortic constriction in animals, along with isoprenaline or angiotensin II stimulation in cellular systems. Baicalin was given in vivo at doses of 15 mg/kg/day or 25 mg/kg/day, while 10 μM baicalin was applied in vitro. Network pharmacology approaches were utilized across multiple databases to pinpoint potential targets of baicalin and heart failure-associated genes, pointing toward involvement of the PI3K–Akt pathway. Molecular docking simulations were performed to examine baicalin’s interaction with p85α. Baicalin exhibited pronounced anti-hypertrophic and anti-fibrotic properties in both in vivo and in vitro settings. Cardiomyocyte cross-sectional area improved from an average of 390 μm² in the HF group to 195 μm² following baicalin treatment. Fibrotic area decreased from 2.8-fold elevation in the HF group to 1.62-fold in the baicalin-treated group. Baicalin exerted notable cardioprotection by suppressing the PI3K signaling cascade through direct interaction with five specific amino acid residues on the p85α regulatory subunit of PI3K. Combining baicalin with a PI3K p110 inhibitor yielded enhanced protective outcomes. Mean ejection fraction rose from 54% in the baicalin-only group to 67% with the combined regimen. This study establishes baicalin as an effective bioactive compound from herbal sources capable of countering isoprenaline-induced cardiac impairment and identifies p85α as a key pharmacological target. The results highlight the promising therapeutic value of baicalin paired with PI3K p110 inhibition in addressing heart failure, underscoring the need for further clinical investigations.
