A synthetic PGC1α co-activator reprograms microglial immunometabolism to preserve cone function in retinal...

Retinitis pigmentosa (RP) is genetically heterogeneous, yet initiating mutations converge on primary rod degeneration followed by cone dysfunction and loss. Activated microglia are implicated in this secondary phase, but whether selective immunometabolic reprogramming of microglia preserves retinal function remains unknown. In human iPSC-derived microglia and retinal CD11b⁺ cells, PGC1α induction suppressed LPS-driven interferon signaling and cytokine release, yet Seahorse analysis and isotopologue tracing showed that energy metabolism remained altered. We therefore fused PGC1α to a multivalent p65-HSF1 module, yielding ~2.5-fold higher nuclear receptor output than native PGC1α and coordinated engagement of oxidative and anti-inflammatory programs in mouse retinal CD11b⁺ cells. Microglia-restricted expression in humanized RHOP347L mice preserved photopic responses through six months, increased retinal thickness and promoted ramified subretinal IBA1⁺ morphology. Microglial immunometabolism thus represents a potentially genotype-independent neuroprotective target in RP, and engineered PGC1α co-activators provide a means to sustain oxidative metabolism under inflammatory pressure.