Serum amyloid A3 aggravates bleomycin-induced pulmonary fibrosis through Krüppel-like factor 6-dependent interlukin-36α expression

Xin-Yi Yang; Ying Liu; Wen Li; Hui-Xing Li; Yu-Wen Zhong; Yu-Han Cao; Tian-Yi Liu; A-Jing Xu; Wei Gu; Qing Liang; Feng Qian; Lei Sun

doi:10.1038/s41401-025-01596-6

Serum amyloid A3 aggravates bleomycin-induced pulmonary fibrosis through Krüppel-like factor 6-dependent interlukin-36α expression

Acta Pharmacol Sin. 2025 Jun 23. doi: 10.1038/s41401-025-01596-6. Online ahead of print.

Authors

Xin-Yi Yang¹, Ying Liu¹, Wen Li¹, Hui-Xing Li¹, Yu-Wen Zhong¹, Yu-Han Cao², Tian-Yi Liu³, A-Jing Xu⁴, Wei Gu⁵, Qing Liang⁶, Feng Qian⁷, Lei Sun⁸

Affiliations

¹ Shanghai Frontiers Science Center of Drug Target Identification and Drug Delivery, Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
² Department of Clinical Medicine, First Clinical School of Medicine, Anhui Medical University, Hefei, 230031, China.
³ Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu, 233030, China.
⁴ Department of Clinical Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200240, China.
⁵ Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, and Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, Bengbu, 233030, China.
⁶ Department of Pharmacy, Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200240, China.
⁷ Shanghai Frontiers Science Center of Drug Target Identification and Drug Delivery, Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China. fengqian@sjtu.edu.cn.
⁸ Shanghai Frontiers Science Center of Drug Target Identification and Drug Delivery, Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China. sunlei_vicky@sjtu.edu.cn.

PMID: 40550960
DOI: 10.1038/s41401-025-01596-6

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease; however, effective clinical treatments for IPF are lacking. High serum amyloid A (SAA) expression in serum is closely related to the severity of pulmonary fibrosis, but the underlying mechanisms remain incompletely understood. This study found that the expression of endogenous SAA3 was significantly induced in mice with bleomycin-induced fibrosis. Saa3 deletion alleviated pulmonary fibrosis in mice. Additionally, recombinant IL-36α treatment aggravated fibrosis in bleomycin-induced Saa3^-/- mice. Furthermore, SAA3 could induce the expression of IL-36α in macrophages through the NF-κB pathway and transcription factor Krűppel-like factor 6 (KLF6). Also, the Klf6 knockdown alleviated severe lung fibrosis after recombinant SAA3 treatment. In conclusion, our study suggested that SAA3 aggravated bleomycin-induced pulmonary fibrosis by inducing IL-36α expression in macrophages through the NF-κB-KLF6 pathway. It provides new theoretical bases and potential therapeutic targets for treating fibrosis-related diseases.

Keywords: IL-36; KLF6; idiopathic pulmonary fibrosis; serum amyloid A3.