Targeting Hspd1 Attenuates Neuroinflammation and Promotes Functional Recovery After Intracerebral Hemorrhage

Background: Intracerebral hemorrhage (ICH) triggers a profound neuroinflammatory cascade in which microglial polarization critically influences secondary brain injury and neurological outcomes. Clinical data revealed that Hspd1 expression is significantly elevated in circulating monocytes from ICH patients and negatively correlates with functional recovery, implicating Hspd1 in disease progression.

Methods: To determine the regulatory role of Hspd1 in microglial function, we performed genetic knockdown of Hspd1 in BV2 microglia and conducted integrated transcriptomic and alternative splicing analyses. Polarization phenotypes were assessed using qPCR, ELISA, immunofluorescence, and flow cytometry. Hspd1-deficient microglia were stereotactically transplanted into a mouse ICH model to evaluate therapeutic efficacy on cerebral edema, hematoma resolution, and neurological outcomes.

Results: Silencing Hspd1 induced broad transcriptomic remodeling and extensive alterations in alternative splicing programs, collectively driving microglia toward an anti-inflammatory M2-like phenotype. Hspd1 knockdown markedly increased IL-10, TGF-β, Arg1, and Ym1 while suppressing IL-6, TNF-α, iNOS, and CCL3. In vivo, transplantation of Hspd1-deficient microglia significantly reduced brain water content, decreased hematoma volume, and improved modified neurological severity scores at multiple time points following ICH.

Conclusion: Hspd1 functions as an upstream master regulator integrating transcriptional and post-transcriptional mechanisms to control microglial polarization. Targeting Hspd1 represents a promising immunomodulatory strategy for mitigating neuroinflammation and enhancing neurological recovery after ICH.

Dr. Ling Yin received her PhD from South China Agricultural University and completed postdoctoral training at Fudan University and the University of Florida College of Medicine. Dr. Yin's research focuses on cancer immunology, gene therapy, and neuroinflammation, with particular emphasis on immune checkpoint regulation and microglial polarization. She has published extensively in journals including The Journal for ImmunoTherapy of Cancer, Frontiers in Immunology, and Drug Discovery Today. Dr. Yin serves on the editorial boards of multiple peer-reviewed journals and has been a Grand Award Judge at the International Science and Engineering Fair (ISEF) for multiple years. She is the recipient of a Global Recognition Award (2024, 2026) and has been recognized as a High-Caliber Talent of Hefei City.