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Insomnia symptoms double the risk of cardiovascular disease (CVD), yet shared genetic pathways remain unclear. Genome-wide association studies (GWAS) identified a genetic locus (near ATP5G1, UBE2Z, SNF8, IGF2BP1, and GIP) linked to insomnia and CVD. We used Drosophila models to perform tissue-specific RNAi knockdowns of four conserved orthologues (ATPSynC, Lsn, Bruce, and Imp) in neurons and the heart. Neuronal-specific knockdown of ATPSynC, Imp, and Lsn impaired sleep quantity and quality. In contrast, cardiac knockdown of ATPSynC and Lsn reduced cardiac function and lifespan, with Lsn knockdown also causing cardiac dilation and myofibrillar disorganization. Cross-tissue effects were evident: neuronal Imp knockdown compromised cardiac function, while cardiac ATPSynC and Lsn knockdown increased sleep fragmentation and inflammation (marked by Upd3 elevation in the heart or head). Overexpression of Upd3 in neurons impaired cardiac function, while its overexpression in the heart disrupted sleep. Our findings reveal conserved genes mediating tissue-specific and cross-tissue interactions between sleep and cardiac function, providing novel insights into genetic mechanisms linking insomnia and CVD through inflammation.