Myeloid FSH-FSHR signaling drives menopause-associated cognitive decline via a mitochondrial RNA-dependent neuroinflammation axis

Menopause-associated cognitive decline is a pervasive health challenge for women, intricately linked to neuroinflammation, yet the precise immunometabolic mechanisms remain largely elusive. Here, we found that follicle-stimulating hormone (FSH) directly promotes neuroinflammation and cognitive deficits in a mouse model of menopause. We uncover that FSH signaling in myeloid cells triggers the cytosolic leakage of mitochondrial RNA (mtRNA) by reducing NAD+ capping at its 5′ or 3’-end. This aberrant mtRNA accumulation subsequently activates the TBK1–IRF3–IFNβ axis. Critically, the RNA-editing enzyme ADARB2 emerges as a key downstream effector of FSH, governing mtRNA localization and double-stranded RNA (dsRNA) formation. Myeloid-specific deletion of Fshr or Adarb2, or pharmacological inhibition of ADARB2 with 8-Azanebularine, robustly rescues neuroinflammation and cognitive impairment in ovariectomized mice. Furthermore, exogenous administration of NAD+-capped mtRNA attenuates FSH-driven neuroinflammation. Our findings define a pathogenic FSH–FSHR pathway in menopause, challenging estrogen-centric views of brain aging, and identify ADARB2 inhibition and NAD+-mtRNA integrity as potent non-estrogenic therapeutic strategies for menopause-associated cognitive decline.