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

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 Qian1, Lei Sun1
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
Correspondence to: Feng Qian: fengqian@sjtu.edu.cn, Lei Sun: sunlei_vicky@sjtu.edu.cn,
DOI: 10.1038/s41401-025-01596-6
Received: 23 February 2025
Accepted: 21 May 2025
Advance online: 23 June 2025

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

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