SLC25A1/CIC supports osteoclastogenesis by coordinating mitochondrial bioenergetics and redox homeostasis.

Osteoclastogenesis requires precise coordination between mitochondrial bioenergetics and anabolic programs, yet the underlying mechanisms remain unclear. Here, we identify the mitochondrial citrate carrier (CIC, encoded by SLC25A1) as a crucial link that couples mitochondrial bioenergetics to glutathione (GSH)-dependent redox regulation during osteoclastogenesis. CIC expression was elevated in the osteoclast-lineage cells  from postmenopausal osteoporosis (PMOP) patients and ovariectomized (OVX) mice, and was positively correlated with classical osteoclast markers. During osteoclastogenesis, CIC was progressively upregulated. Pharmacologic inhibition of CIC with CTPI-2 not only suppressed osteoclastogenesis but also disrupted core metabolic processes, including tricarboxylic acid cycle engagement, amino acid biosynthesis, and mitochondrial respiration. Integrative transcriptomic and metabolomic profiling further revealed a compensatory shift toward enhanced GSH synthesis. Mechanistically, CIC associated with the glutamate-cysteine ligase modifier subunit (GCLM), linking mitochondrial metabolic regulation to the GSH synthetic machinery. CIC inhibition increased GCL activity, intracellular GSH content, and the GSH/GSSG ratio, accompanied by reduced reactive oxygen species accumulation. The functional importance of the GSH axis was evident, as GCL inhibition by buthionine sulfoximine partially reversed the anti-osteoclastogenic effects of CIC inhibition. Consistently, osteoclast-targeted silencing of CIC in OVX mice mitigated bone loss. Collectively, these findings support a role for CIC as a metabolic integrator of energy and redox metabolism in osteoclasts, and highlight its potential as a candidate target for limiting excessive bone resorption in PMOP.