Abstract: FR-PO0076
Palmitoylated Pyruvate Kinase M2 Drives Cyst Growth in ADPKD Through Extracellular Vesicle-Mediated Microenvironmental Remodeling
Session Information
- ADPKD and Cystic Kidney Disease - 2
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)
Authors
- Lei, Qunjuan, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Li, Xiaogang, Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background
ADPKD is characterized by progressive cyst expansion accompanied by metabolic abnormalities, inflammation, and fibrosis. Although metabolic reprogramming and extracellular vesicle (EV)-mediated communication have been implicated in disease progression, the mechanisms linking these processes remain poorly understood. In addition, the role of pyruvate kinase M2 (PKM2), the final rate-limiting enzyme of glycolysis, in these processes remains undefined.
Methods
PKM2 expression, palmitoylation, and EV secretion were examined in Pkd1 mutant cells, mouse models, and human ADPKD kidneys. EVs were isolated and characterized, and their functional effects were assessed in vitro and in vivo. Genetic deletion and pharmacologic inhibition of PKM2 were used to evaluate its role in cyst progression.
Results
PKM2 was markedly upregulated in Pkd1 mutant renal epithelial cells and ADPKD kidneys. Kidney-specific deletion of Pkm2 or pharmacologic inhibition with PKM2-IN-1 significantly reduced cyst growth, inflammation, and fibrosis in multiple mouse models. Mechanistically, intracellular PKM2 promoted epithelial cell proliferation via activation of STAT3, AMPK/S6, and NF-κB p65 signaling. We further show that PKM2 undergoes ZDHHC2-dependent palmitoylation at Cys424 in Pkd1 mutant cells, a modification that facilitates its incorporation into EVs. Inhibition of palmitoylation with 2-bromopalmitate markedly alleviated PKM2 palmitoylation and decreased its loading into EVs. EV-associated PKM2, particularly within large EVs, is subsequently transferred to recipient cells, such as macrophages, where it induces macrophage activation, inflammatory cytokine production, and PD-L1-mediated immune suppression, thereby amplifying the pro-cystogenic microenvironment. Consistently, EVs derived from Pkd1 mutant epithelial cells accelerate cyst progression in vivo, whereas depletion of PKM2 from these EVs markedly attenuates their pathogenic effects, establishing PKM2 as a critical effector cargo.
Conclusion
PKM2 functions as a central metabolic and paracrine regulator in ADPKD, linking metabolic reprogramming to EV-mediated intercellular signaling. ZDHHC2-dependent palmitoylation controls PKM2 EV packaging and downstream multicellular remodeling. Targeting the ZDHHC2–PKM2–EV axis as a novel and therapeutically actionable pathway for ADPKD.
Funding
- NIDDK Support