Diabetic nephropathy (DN) has emerged as the leading cause of end-stage renal disease, with oxidative stress injury and excessive autophagy implicated in its pathogenesis. Elevated levels of the ITIH3 protein are considered closely associated with kidney-related diseases. However, the role of ITIH3 in the progression of DN remains unclear. By collecting peripheral blood from patients with DN, establishing a type 2 diabetic mouse model induced by streptozotocin (STZ), and exposing renal tubular epithelial cells (RTECs) to high glucose (HG) conditions, we comprehensively investigated the role of ITIH3 in DN at clinical, animal, and cellular levels. The ITIH3 level in DN patients' peripheral blood was elevated and positively correlated with inflammatory markers. At the cellular level, HG stimulation upregulated ITIH3 in RTECs, enhancing apoptosis, fibrosis, inflammation, oxidative stress, and autophagy, while silencing ITIH3 suppressed these damages. Molecularly, silencing ITIH3 upregulated HSP90B1, increased STAT3 ubiquitination, and inhibited its activation; silencing HSP90B1 reversed ITIH3-silencing's benefits, and overexpressing STAT3 counteracted HSP90B1-overexpression's effects. At the animal level, DN mice showed elevated blood glucose, renal hypertrophy, impaired function, and increased fibrosis, inflammation, and autophagy, whereas ITIH3 silencing reduced blood glucose and alleviated these abnormalities. Our research findings reveal that silencing ITIH3 up-regulates HSP90B1, which in turn elevates the ubiquitination level of STAT3 and suppresses its activation. This, consequently, inhibits oxidative stress and autophagy in RTECs. These results offer a promising therapeutic approach for the treatment of DN.
