Flavonoids from <i>Elsholtzia ciliata</i> restore redox electron flow and metabolic signaling via PTP1B inhibition in muscle and liver cells

PTP1B is a key negative regulator of insulin and leptin signalling and a promising therapeutic target for metabolic dysfunction, yet no clinically approved inhibitor exists due to selectivity and bioavailability challenges. To identify novel natural PTP1B inhibitors from Elsholtzia ciliata and evaluate their efficacy in reversing hormonal resistance and redox imbalances in skeletal muscle and hepatic models. Four flavonoids (EC2–EC5) were assessed via PTP1B inhibition assays, molecular docking, glucose uptake, qRT-PCR, and NAD(H)/NADP(H) quantification in palmitate-treated C2C12 myotubes and Hepa1c1c7 hepatocytes. All compounds potently inhibited PTP1B (IC50 < 5.4 µM). EC2 showed the strongest activity and normalised redox imbalances, while EC5 exhibited the highest binding affinity and restored multi-hormone responsiveness, potentially through PTP1B inhibition combined with AMPK pathway engagement. EC2 and EC5 represent promising natural PTP1B inhibitors partially restoring metabolic homeostasis and multi-hormone responsiveness in vitro, highlighting their potential for insulin resistance and metabolic syndrome.