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Zhenzhen Li,1,&ast; Cong Sun,2,&ast; Qing Zhang,1,&ast; Lifan Ji,3 Yiting Zhang,1 Shuo Li,1 Mengmeng Gu,1 Jie Gao,1 Zhihui Huang,1 Meng Wang,1 Junshan Zhou,1 Lin Zhu,1 Teng Jiang,1 Qing Zhou,4 Qiwen Deng1 1Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 3School of Basic Medicine and Clinical Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China; 4NHC Key Laboratory of Contraceptives Vigilance and Fertility Surveillance, Jiangsu Health Development Research Center, Jiangsu Provincial Medical Key Laboratory of Fertility Protection and Health Technology Assessment, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiwen Deng, Department of Neurology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, People’s Republic of China, Tel +8602552271000, Fax +8602552271000, Email qiw_deng@njmu.edu.cn Qing Zhou, NHC Key Laboratory of Contraceptives Vigilance and Fertility Surveillance, Jiangsu Health Development Research Center, Jiangsu Provincial Medical Key Laboratory of Fertility Protection and Health Technology Assessment, No. 277 Fenghuang West Street, Nanjing, Jiangsu, 210036, People’s Republic of China, Tel +86-25-86576036, Fax +86-25-86576036, Email 863840726@qq.comBackground: Acute ischemic stroke (AIS) triggers a complex systemic immune-inflammatory response. While proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provide significant lipid-lowering and pleiotropic anti-inflammatory effects, their impact on early peripheral inflammatory and immune responses in AIS patients due to large artery atherosclerosis (LAA) remains underexplored.Methods: A total of 72 AIS patients attributed to LAA were included in the final analysis of this prospective study (the standard treatment group, n = 24; the intensive treatment group, n = 48). Fasting blood samples were obtained at admission and the 2-week follow-up. A comprehensive panel of laboratory parameters was assessed at baseline and the 2-week follow-up, encompassing lipid profiles, a spectrum of inflammatory biomarkers (including but not limited to high-sensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)), and lymphocyte subsets.Results: The intensive treatment group achieved a significantly greater reduction in low-density lipoprotein cholesterol (LDL-C) compared to the standard treatment group (P < 0.001). Notably, the intensive treatment group also showed significant reductions in key pro-inflammatory cytokines IL-6 (P = 0.024) and TNF-α (P = 0.041). However, no significant between-group differences were observed in the changes of peripheral blood lymphocyte subsets (P > 0.050).Conclusion: In AIS patients, early adjunctive PCSK9 inhibitor therapy provides superior lipid-lowering and may modulate specific pro-inflammatory cytokines compared to statin monotherapy, without significantly altering peripheral lymphocyte subset distributions within 2 weeks. Further large-scale studies are warranted to validate its immunomodulatory role and long-term clinical outcomes.Trial Registration: ClinicalTrials.gov NCT05410457. Registered May 24, 2022. https://www.clinicaltrials.gov/ct2/show/NCT05410457; ClinicalTrials.gov NCT05397405. Registered May 23, 2022. https://www.clinicaltrials.gov/ct2/show/NCT05397405.Plain Language Summary: Acute ischemic stroke (AIS) triggers a complex systemic immune-inflammatory response. While proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors provide significant lipid-lowering and pleiotropic anti-inflammatory effects, their impact on early peripheral inflammatory and immune responses in AIS patients due to large artery atherosclerosis (LAA) remains underexplored. Our study evaluated the early immunomodulatory effects of PCSK9 inhibitor add-on therapy versus statin monotherapy in acute ischemic stroke patients. The combination therapy achieved superior LDL-C reduction and significantly decreased key pro-inflammatory cytokines (IL-6 and TNF-α), while no significant impact on peripheral lymphocyte subset distributions was observed within 2 weeks. The image shows a schematic overview and four graphs. The schematic shows two treatment groups: PCSK9 inhibitor plus statin (the intensive treatment group) versus statin alone (the standard treatment group). Blood samples were taken at baseline and after a 2-week follow-up and analyzed for cytokines and lymphocyte subsets. Graphs A-D compare the effects of the two treatments. Graph A shows IL-6 changes and graph B shows TNF-alpha changes, both with significant differences. Graphs C and D show changes in total and helper lymphocytes, with no significant differences. All graphs use violin plots to display data distribution for each treatment group.Diagram of PCSK9 inhibitor plus statin versus statin alone on cytokines and lymphocyte subsets with four graphs comparing changes from baseline to 2-week follow-up.Keywords: acute ischemic stroke, PCSK9 inhibitor, cytokines, lymphocyte subsets, inflammation, immunomodulation
