Intersection of Regulatory Analysis and Signature Reversion Uncovers Therapeutic Drugs and Targets for SETBP1-HD

BackgroundSETBP1 haploinsufficiency disorder (SETBP1-HD) is a neurodevelopmental condition characterized by developmental delay, speech apraxia, motor deficits, and autism spectrum disorder (ASD), caused by deficiency of the transcription factor (TF) SETBP1. Since current management is limited to symptomatic relief, we defined a robust consensus molecular signature for SETBP1-HD and prioritized drugs that converge with SETBP1 regulatory targets. MethodsWe performed a meta-analysis of three independent transcriptomic datasets derived from in vitro models of SETBP1 deficiency. Using Robust Rank Aggregation (RRA), we overcame transcriptomic heterogeneity to establish a SETBP1-HD consensus signature. We integrated this signature with known and spatio-temporal-aware SETBP1 interactions to prioritize key regulatory and drug targets. Finally, we screened the LINCS L1000 drug perturbation database for compounds capable of reversing the consensus SETBP1-HD gene signature. ResultsOur regulatory analysis yielded potential, critical therapeutic windows, while our consensus analysis identified LIN28A (a key regulator of developmental timing) and SPON1 ( F-spondin) as novel, robustly upregulated targets across models. LIN28A provides a potential mechanism for the dysregulated neurogenesis and progenitor proliferation observed in patient-derived cells, while SPON1 links molecular dysfunction to motor and connectivity deficits seen in patients. Our in silico drug repurposing screens prioritized celecoxib and buspirone as top therapeutic candidates. Mechanistically, celecoxib targets the prioritized SETBP1 regulatory target COX-2 (PTGS2) to mitigate neuroinflammation, while the potent neuromodulator buspirone chemically stabilizes vulnerable circuits to correct the underlying neurotransmitter imbalance driven by SETBP1 loss. LimitationsThis study relies on in silico consensus modeling derived from cell culture and animal models. While robust statistical thresholds were applied, the therapeutic efficacy of the identified candidates on behavioral phenotypes--specifically motor deficits and speech apraxia--requires in vivo validation. Additionally, the specific contribution of LIN28A to the ASD phenotype warrants further functional characterization. ConclusionsWe defined a unified molecular mechanism for SETBP1-HD, in which dosage deficiency leads to a delayed neurogenic state driven by LIN28A, coupled with connectivity defects driven by SPON1, ultimately resulting in a destabilized excitation/inhibition balance. We identify celecoxib and buspirone as top therapeutic candidates, offering an immediate translational pathway to address the core neurodevelopmental, circuitry, and motor challenges associated with SETBP1-HD variants.