NRF2 activation attenuates obesity-induced adipose inflammation by suppressing STING signaling, with depot-specific regulation

Abstract

Obesity-induced oxidative stress triggers the cGAS-STING pathway via mitochondrial DNA (mtDNA) leakage, driving chronic white adipose tissue (WAT) inflammation. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of antioxidant responses, but whether it can serve as an endogenous negative regulator of the STING-driven inflammatory cascade in adipocytes remains poorly defined. This study investigated the role of NRF2 in modulating the STING pathway to alleviate adipose inflammation and explored how fat depot heterogeneity influences this regulatory axis. NRF2 activity was assessed in the WAT of high-fat diet-induced obese mice and in differentiated adipocytes. In vitro, palmitic acid-stimulated adipocytes were used to evaluate the anti-inflammatory effects of NRF2 activation. Mechanistic studies involved genetic knockdown/overexpression, transcriptomic profiling, and assessments of cytosolic mtDNA levels and STING translocation. In vivo, obese mice were treated with the NRF2 activator CDDO-Im, alongside in situ AAV-pAdipoq-mediated NRF2 knockdown or STING overexpression in WAT, to assess metabolic phenotypes and inflammatory responses. NRF2 activity was reduced in obese WAT and mature adipocytes. In vitro, NRF2 activation attenuated oxidative stress and inflammation by suppressing the STING cascade, characterized by diminished cytosolic mtDNA leakage and subsequent inhibition of STING-dependent translocation and effector signaling. In vivo, pharmacological NRF2 activation significantly improved obesity, insulin resistance, and systemic inflammation. These effects were largely abolished by local adipocyte-specific NRF2 knockdown or STING overexpression. Transcriptomic profiling revealed depot-specific effects: NRF2 robustly suppressed inflammatory pathways in visceral epididymal WAT (eWAT) but had minimal impact in subcutaneous inguinal WAT (iWAT). Consistently, NRF2 downregulated STING in eWAT while upregulating it in iWAT. Multiplex imaging and cell-fraction analysis demonstrated that active STING signaling operates predominantly in mature adipocytes. Adipocyte differentiation status was identified as a key determinant of this divergence. Due to higher adipogenic potential, NRF2 preferentially inhibited adipogenesis in iWAT, leading to an enrichment of immature adipocytes expressing high STING levels. NRF2 is a critical negative regulator of STING signaling that mitigates obesity-associated inflammation. This study identifies the NRF2–STING axis as a therapeutic target and demonstrates that inherent differences in adipogenicity dictate depot-specific pharmacological responses, providing a framework for precision translational medicine in metabolic diseases.