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Background: Modified Si-Miao granule (mSMG), a traditional Chinese medicine, is beneficial for T2DM and insulin resistance (IR), but the underlying mechanism remains unknown. Methods: Using network pharmacology, we screened the compounds of mSMG and identified its targets and pathway on hepatic IR in T2DM. Using molecular docking, we identified the affinity between the compounds and hub target TNF-α. Then these were verified in KK-Ay mice and HepG2 cells. Results: 50 compounds and 170 targets of mSMG against IR in T2DM were screened, and 9 hub targets such as TNF and MAPK8 were identified. 170 targets were mainly enriched in insulin resistance and TNF pathway, so we speculated that mSMG might act on TNF-α, JNK1 and then regulate insulin signaling to mitigate IR. Experimental validation proved that mSMG ameliorated hyperglycemia, IR, and TNF-α, enhanced glucose consumption and glycogen synthesis, relieved the phosphorylation of JNK1 and IRS-2 (Ser388), and elevated the phosphorylation of Akt (Ser473) and GSK-3β (Ser9) and GLUT2 expression in KK-Ay mice. Molecular docking further showed berberine from mSMG had excellent binding capacity with TNF-α. Then, in vitro validation experiments, we found that 20% mSMG-MS or 50 μM berberine had little effect in IR-HepG2 cell viability, but significantly increased glucose consumption and glycogen synthesis and regulated TNF-α/JNK1/IRS-2 pathway. Conclusion: Network pharmacology and molecular docking help us predict potential mechanism of mSMG and further guide experimental validation. mSMG and its representative compound berberine improve hepatic IR and glycogen synthesis, and its mechanism may be related to the inhibition of TNF-α/JNK1/IRS-2 pathway. [ABSTRACT FROM AUTHOR]