Targeting BTK Reprograms Macrophage Lactylation via the HIF-1α-Glycolysis-Rap1a Axis to Attenuate Ischemic Acute Kidney Injury

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Abstract Title *

Targeting BTK Reprograms Macrophage Lactylation via the HIF-1α-Glycolysis-Rap1a Axis to Attenuate Ischemic Acute Kidney Injury

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Co-author 1

Yannan Zhang zhangyannan@gdph.org.cn Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Medical Research Institute Guangzhou China *

Co-author 2

Qi Liu liuqi000814@163.com Southern Medical University School of Medicine Guangzhou China -

Co-author 3

Jiannan He hejiannan@gdph.org.cn Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Department of Kidney Transplantation Guangzhou China -

Co-author 4

Yongxian Zheng zhengyx0930@foxmail.com Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Department of Kidney Transplantation Guangzhou China -

Co-author 5

Xinyue Zeng zengxinyue0725@qq.com Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Guangdong Cardiovascular Institute Guangzhou China -

Co-author 6

Yue Zhou zhouyuesjd@163.com Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Guangdong Cardiovascular Institute Guangzhou China -

Co-author 7

Qiquan Sun sunqiquan@gdph.org.cn Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Department of Kidney Transplantation Guangzhou China -

Co-author 8

Co-author 9

Co-author 10

Co-author 11

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Introduction

Acute kidney injury (AKI), usually caused by ischemic-reperfusion injury (IRI), poses a major global health challenge with high morbidity and mortality. Clinical strategies remain limited. Macrophages play a pivotal role in the inflammatory response during AKI. Bruton's tyrosine kinase (BTK) is a critical component in various immune receptor signaling pathways.

Methods

We evaluated BTK expression in murine/human AKI kidneys. In vivo, we constructed a mouse IRI model, and BTK knockout and drug inhibition were observed as intervention groups. In vitro we employed RAW264.7 macrophage cell line and bone marrow-derived macrophages (BMDMs) to examine macrophage polarization, chemotaxis, and inflammatory cytokine production following BTK inhibition. Mechanisms were explored via lactylation assays and CUT&Tag.

Results

We for the first time showed intra-renal macrophages highly express BTK in acute AKI, both in mice and human. BTK Inhibition selectively suppressed M1 macrophage polarization via HIF-1α-glycolysis disruption, reducing proinflammatory mediators. Mechanistically, BTK inhibition decreased H3K18 lactylation, modulating key activation gene Rap1a. Both genetic Btk knockout and two clinical available BTK inhibitors, Zanubrutinib and Ibrutinib, remarkably alleviated ischemic injury and following fibrosis in mouse models.

Conclusion

这些结果表明BTK在M1巨噬细胞介导的炎症中起核心作用并将其确定为选择性M1抑制的新靶点，并提供一种易于翻译的AKI治疗策略，具有显著的潜力便于临床快速实施。These findings demonstrated BTK's central role in M1 macrophage-mediated inflammation and established it as a novel target for selective M1 inhibition, and provided a readily translatable therapeutic strategy for AKI, with significant potential for rapid clinical implementation.

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