{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T15:27:29Z","timestamp":1788535649666,"version":"build-2803163510"},"reference-count":93,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Nephrolithiasis associated with metabolic syndrome represents a growing global public health burden with a 5-year recurrence rate of up to 50%. Current first-line preventive strategies, primarily potassium citrate and thiazide diuretics, only correct urinary chemical abnormalities symptomatically, and patient adherence remains below 50% at 1\u00a0year. Importantly, these approaches fail to address the core pathological basis of tubular injury driven by metabolic dysregulation. Mitochondrial dysfunction is the central mechanistic hub linking systemic metabolic stress to intrarenal lithogenic susceptibility. In the setting of metabolic syndrome, impaired mitochondrial biogenesis and excessive mitochondrial reactive oxygen species (mtROS) production in renal tubular epithelial cells activate the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, establishing a self-perpetuating vicious cycle of \u201cmetabolic disturbance, mitochondrial damage, inflammatory amplification, calcium oxalate crystal deposition'. This core pathogenic loop has not been targeted by existing therapeutic strategies. Liraglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), exerts pleiotropic renoprotective effects independent of its canonical glucose-lowering actions. It coordinately activates peroxisome proliferator-activated receptor gamma coactivator-1\u03b1 (PGC-1\u03b1) through two complementary pathways: transcriptional upregulation through the PKA\/CREB axis, and post-translational deacetylation via the AMPK\/SIRT1 pathway. This dual activation restores mitochondrial homeostasis, reprograms tubular lipid metabolism, attenuates oxidative stress, and suppresses inflammatory cascades. This review is the first to systematically integrate the mitochondrial pharmacology of liraglutide with the pathophysiology of nephrolithiasis. It critically appraises the strengths and limitations of preclinical and clinical evidence, identifies key knowledge gaps in the field, and proposes a phased translational research roadmap encompassing mechanistic validation, biomarker development, and clinical trial design. This work provides a solid theoretical foundation for repurposing GLP-1RAs for the prevention of this condition.<\/jats:p>","DOI":"10.3389\/fphar.2026.1903973","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T15:05:46Z","timestamp":1788534346000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Liraglutide and renal mitochondrial homeostasis: targeting the \u201cmetabolism-inflammation-lithogenesis\u201d axis in metabolic syndrome"],"prefix":"10.3389","volume":"17","author":[{"given":"Fei","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Child Healthcare and Rehabilitation, The Second Hospital & Clinical Medical School, Lanzhou University","place":["Lanzhou, China"]},{"name":"Department of Endocrinology, The Second Hospital & Clinical Medical School, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, Key Laboratory of Disease of Urological Systems, Gansu Nepho-Urological Clinical Center, The Second Hospital & Clinical Medical School, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Urology, Key Laboratory of Disease of Urological Systems, Gansu Nepho-Urological Clinical Center, The Second Hospital & Clinical Medical School, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyan","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Urology, Key Laboratory of Disease of Urological Systems, Gansu Nepho-Urological Clinical Center, The Second Hospital & Clinical Medical School, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoji","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Urology, Key Laboratory of Disease of Urological Systems, Gansu Nepho-Urological Clinical Center, The Second Hospital & Clinical Medical School, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqiang","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Urology, Key Laboratory of Disease of Urological Systems, Gansu Nepho-Urological Clinical Center, The Second Hospital & Clinical Medical School, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The Second Hospital & Clinical Medical School, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiqi","family":"He","sequence":"additional","affiliation":[{"name":"Department of Urology, Key Laboratory of Disease of Urological Systems, Gansu Nepho-Urological Clinical Center, The Second Hospital & Clinical Medical School, Lanzhou University","place":["Lanzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e194752","DOI":"10.1172\/JCI194752","article-title":"Signaling architecture of the glucagon-like peptide-1 receptor","volume":"136","author":"Austin","year":"2026","journal-title":"J. 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