Objectives Natural Killer (NK) cell dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis, but the underlying mechanisms remain poorly understood. This study investigates immunometabolic alterations in NK cells from SLE patients and explores therapeutic strategies for their restoration. Methods We characterized mitochondrial structure and function in NK cells from the peripheral blood of SLE patients and healthy controls using flow cytometry, electron microscopy, and proteomics. Key mitophagy-related gene expressions were quantified using qPCR. The ability of hydroxychloroquine (HCQ) to restore mitochondrial recycling and NK cell function were assessed in vitro. Results SLE NK cells displayed accumulated enlarged, hyperpolarized mitochondria with cristae disorganization, and reduced mitophagy. Impaired lysosomal acidification and mtDNA extrusion into the cytosol were also observed. Treatment with HCQ restored mitochondrial recycling, and NK cell effector functions, including cytokine production and cytotoxicity by acidifying lysosomes. Conclusions This study identifies mitochondrial recycling dysfunction as a driver of NK cell abnormalities in SLE patients. HCQ can correct these abnormalities by acidifying the lysosomes and highlights the potential of HCQ to restore NK cell functionality. These findings provide new insights into the immunometabolic mechanisms underlying SLE and suggest avenues for targeted therapeutic interventions.

The authors have declared no competing interest.

This work was funded by a grant from the Swiss National Science Foundation Ambizione PZ00P3_173950 (DC), a grant from the Novartis Foundation 173950 (DC), a grant from the National Science Foundation 310030_200796 (AJ) and PHS NIH R01AI148161 (GCT).

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Ethics committee/IRB of Lausanne University Hospital (Commission cantonale d'ethique de la recherche sur l'etre humain - CER-VD, Lausanne, Switzerland) gave ethical approval for this work

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