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

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.