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Supplemental studies have shed light on the upstream mechanism of this signaling pathway, demonstrating that sUA provokes IR in HUA by stimulating the Nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme Oxygenase 1(HO-1) signaling pathway and upregulating the regulatory thioredoxin interacting protein (TXNIP), thereby inhibiting the IRS2/PI3K/AKT signaling pathway in macrophages (57)

This oxidative burden impairs insulin receptor signaling through serine phosphorylation of IRS, fostering systemic insulin resistance and compensatory hyperinsulinemia (75)

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