A new LKB1 activator, piericidin analogue S14, retards renal fibrosis through promoting autophagy and mitochondrial homeostasis in renal tubular epithelial cells

Theranostics. 2022 Oct 9;12(16):7158-7179. doi: 10.7150/thno.78376. eCollection 2022.


Background: Liver kinase B1 (LKB1) is the key regulator of energy metabolism and cell homeostasis. LKB1 dysfunction plays a key role in renal fibrosis. However, LKB1 activators are scarce in commercial nowadays. This study aims to discover a new drug molecule, piericidin analogue S14 (PA-S14), preventing renal fibrosis as a novel activator to LKB1. Methods: Our group isolated PA-S14 from the broth culture of a marine-derived Streptomyces strain and identified its binding site. We adopted various CKD models or AKI-CKD model (5/6 nephrectomy, UUO, UIRI and adriamycin nephropathy models). TGF-β-stimulated renal tubular cell culture was also tested. Results: We identified that PA-S14 binds with residue D176 in the kinase domain of LKB1, and then induces the activation of LKB1 through its phosphorylation and complex formation with MO25 and STRAD. As a result, PA-S14 promotes AMPK activation, triggers autophagosome maturation, and increases autophagic flux. PA-S14 inhibited tubular cell senescence and retarded fibrogenesis through activation of LKB1/AMPK signaling. Transcriptomics sequencing and mutation analysis further demonstrated our results. Conclusion: PA-S14 is a novel leading compound of LKB1 activator. PA-S14 is a therapeutic potential to renal fibrosis through LKB1/AMPK-mediated autophagy and mitochondrial homeostasis pathways.

Keywords: AMPK; LKB1; PA-S14; autophagy; renal fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases* / metabolism
  • Autophagy
  • Doxorubicin
  • Epithelial Cells / metabolism
  • Fibrosis
  • Homeostasis
  • Humans
  • Renal Insufficiency, Chronic*
  • Transforming Growth Factor beta


  • AMP-Activated Protein Kinases
  • AMP-Activated Protein Kinase Kinases
  • Doxorubicin
  • Transforming Growth Factor beta