Cathepsin B regulated via TFEB and lysosomal membrane permeabilization in adipose tissue macrophages aggravates obesity-related severe acute pancreatitis

  • Int Immunopharmacol. 2026 Jul 1:180:116695. doi: 10.1016/j.intimp.2026.116695.
Xin Ling  1 ,  Chaoqun Han  2 ,  Liping Sheng  3 ,  Zhen Ding  4
Affiliations
  • 1. Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: [email protected].
  • 2. Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3. Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Gastroenterology, the First Affiliated Hospital, Xiamen University, Xiamen, China.
  • 4. Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: [email protected].
PMID: 42019387 DOI: 10.1016/j.intimp.2026.116695
Abstract

Objectives: Obesity is recognized as a risk factor for severe acute pancreatitis (SAP). Adipose tissue macrophages (ATMs) have been identified to perform an important role in the development of obesity-related SAP. This study aims to investigate the mechanism through which obesity intensifies the severity of SAP.

Methods: High-fat diet was used to induce obese mice. Then mice were subjected to SAP induction through the administration of caerulein and lipopolysaccharide. CA-074me was used as an inhibitor of Cathepsin B (CTSB) activity, while transcription factor EB (TFEB) activator 1/C1 was used to facilitate the nuclear translocation of TFEB. Inflammatory injuries within pancreatic and adipose tissue were evaluated. Expressions of NOD-like Receptor family pyrin domain-containing 3 (NLRP3), Caspase1, and CTSB were quantified. In addition, TFEB nuclear translocation and lysosomal membrane permeabilization (LMP) was evaluated.

Results: Increased inflammatory injuries of pancreas and adipose tissue in obesity-related SAP were observed. This coincided with the activation of the NLRP3-Caspase1 pathway and increased level of mature CTSB in ATMs. CTSB inhibition resulted in alleviation of SAP and a reduction in the expression of the NLRP3-Caspase1 pathway. Obesity stimulated nuclear translocation of TFEB in ATMs that was associated with increased CTSB. Besides, LMP was induced in ATMs, leading to increased mature CTSB releasing from lysosomes.

Conclusion: Obesity could stimulate nuclear translocation of TFEB in ATMs resulting in upregulated level of CTSB. Induced LMP leaded to increased mature CTSB releasing from lysosomes. Mature CTSB further aggravated obesity-related SAP by activating the NLRP3-Caspase1 pathway.

Keywords
Adipose tissue macrophages; Cathepsin B; Lysosomal membrane permeabilization; Obesity related severe acute pancreatitis; Transcription factor EB.
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