ArticleTheranostics2024
Palmitoylation of PKCδ by ZDHHC5 in hypothalamic microglia presents as a therapeutic target for fatty liver disease.
Article in Theranostics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 30 citations in OpenAlex.
- cGAS-STING as a Neuroimmune Traffic Molecule: Unraveling Pathogenic Mechanisms and Therapeutic Potential in Neurological Disorders.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2026Review
- Hypothalamic Control of Liver Health and Disease: From Circuits to Pathophysiology and Therapies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Research Progress on Anti-Inflammatory and Antioxidant Mechanism of Artemether Based on MAPK/NF-κB Signaling Pathway.International journal of molecular sciences · 2026Review
- Multi-target regulation by artemether in MAFLD through EGFR/HSP90 pathways.Journal of advanced research · 2026Article
- M6A-modified circArhgap26 attenuates cardiac ischemia‒reperfusion injury by suppressing plakophilin-1 palmitoylation.Signal transduction and targeted therapy · 2026Article
- The Emerging Roles of Protein Lipidation in Fertility and Reproductive Disorders: Mechanisms and Therapeutic Implications.Biomolecules · 2026Review
- Lactobacillus reuteri targets farnesoid X receptor-dependent bile acid homeostasis to ameliorate alcoholic liver disease.The ISME journal · 2026Article
- Bioinformatics Analysis of ZDHHC-protein Acyltransferase for Predicting the Rupture of Aneurysmal Subarachnoid Hemorrhage.Current neurovascular research · 2026Article
- Protein S-acylation: Pathological mechanisms and novel therapeutic targets for diabetic complications.Chinese herbal medicines · 2026Review
- ZDHHC5 and ZDHHC14 promote depression via the mediation of double-negative T cells.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Article
- Small-molecule probes based on natural products: Elucidation of drug-target mechanisms in stroke.Journal of pharmaceutical analysis · 2025Review
- Protein Kinase C Family: Structures, Biological Functions, Diseases, and Pharmaceutical Interventions.MedComm · 2025Review
- Recent advances in S-palmitoylation and its emerging roles in human diseases.Journal of hematology & oncology · 2025Review
- Artemisinin and Its Derivatives from Molecular Mechanisms to Clinical Applications: New Horizons Beyond Antimalarials.International journal of molecular sciences · 2025Review
- Target discovery-directed pharmacological mechanism elucidation of bioactive natural products.Medical review (2021) · 2025Review
- Role of S-palmitoylation in digestive system diseases.Cell death discovery · 2025Review
- Palmitoylation in cardiovascular diseases: Molecular mechanism and therapeutic potential.International journal of cardiology. Heart & vasculature · 2025Review
- Mechanisms and functional implications of ZDHHC5 in cellular physiology and disease.Journal of lipid research · 2025Review
- Regulation and Function of the cGAS-STING Pathway: Mechanisms, Post-Translational Modifications, and Therapeutic Potential in Immunotherapy.Drug design, development and therapy · 2025Review
- Neuronal injury and hepatotoxicity: astrocytes and stellate cells convergence and their role in tissue repair.Frontiers in neuroscience · 2025Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The hypothalamus plays a fundamental role in controlling lipid metabolism through neuroendocrine signals. However, there are currently no available drug targets in the hypothalamus that can effectively improve human lipid metabolism. In this study, we found that the antimalarial drug artemether (ART) significantly improved lipid metabolism by specifically inhibiting microglial activation in the hypothalamus of high-fat diet-induced mice. Mechanically, ART protects the thyrotropin-releasing hormone (TRH) neurons surrounding microglial cells from inflammatory damage and promotes the release of TRH into the peripheral circulation. As a result, TRH stimulates the synthesis of thyroid hormone (TH), leading to a significant improvement in hepatic lipid disorders. Subsequently, we employed a biotin-labeled ART chemical probe to identify the direct cellular target in microglial cells as protein kinase Cδ (PKCδ). Importantly, ART directly targeted PKCδ to inhibit its palmitoylation modification by blocking the binding of zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5), which resulted in the inhibition of downstream neuroinflammation signaling. In vivo, hypothalamic microglia-specific PKCδ knockdown markedly impaired ART-dependent neuroendocrine regulation and lipid metabolism improvement in mice. Furthermore, single-cell transcriptomics analysis in human brain tissues revealed that the level of PKCδ in microglia positively correlated with individuals who had hyperlipemia, thereby highlighting a clinical translational value. Collectively, these data suggest that the palmitoylation of microglial PKCδ in the hypothalamus plays a role in modulating peripheral lipid metabolism through hypothalamus-liver communication, and provides a promising therapeutic target for fatty liver diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.