{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:05:52Z","timestamp":1790701552219,"version":"4.1.0"},"reference-count":36,"publisher":"IMR Press","issue":"9","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Project of Guangdong Provincial Bureau of Traditional Chinese Medicine","award":["20254086"],"award-info":[{"award-number":["20254086"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Intervertebral disc degeneration (IDD) is a primary cause of low back pain, closely associated with the senescence of nucleus pulposus cells (NPCs). Energy metabolism disorders and lactate accumulation are observed in degenerated intervertebral discs. However, the molecular mechanism through which lactate accumulation induces IDD and its upstream regulatory factors remain unclear. Methods: Clinical degenerated intervertebral disc tissues were collected. Lactate content was measured using the water-soluble tetrazolium salt-8 (WST-8) method, and the expression of nicotinamide phosphoribosyltransferase (NAMPT) and sirtuin 2 (SIRT2) was analyzed by western blotting. NPCs were cultured in vitro and treated with lactate. Lactate levels, protein lactylation, p38 mitogen-activated protein kinase (p38-MAPK) pathway activity, and cellular senescence were assessed using lactate assay kits, western blotting, and senescence-associated \u03b2-galactosidase staining, respectively. Furthermore, small interfering RNA (siRNA) and overexpression plasmids were used to regulate NAMPT expression, combined with SIRT2 activators or inhibitors, to explore the role of the NAMPT\/SIRT2 axis in regulating lactate metabolism and cellular senescence. Results: Lactate was detected in all four degenerated intervertebral disc tissue samples examined, with variable levels among individuals. NAMPT and SIRT2 protein expression showed similar expression patterns across these samples, suggesting a potential relationship that warrants further investigation in larger cohorts. In vitro experiments confirmed that lactate treatment significantly elevated global protein lactylation levels, activated the p38-MAPK pathway, and induced cellular senescence in NPCs. Knockdown of NAMPT expression reduced lactate and NAD+ levels. Notably, treatment with a SIRT2 activator partially restored the decrease in lactate content but had no significant effect on nicotinamide adenine dinucleotide (NAD+) levels. Overexpression of NAMPT led to lactate accumulation and cellular senescence, both of which could be antagonized by either a lactate inhibitor or a SIRT2 inhibitor. Conclusions: In vitro experiments indicate that NAMPT appears to modulate lactate metabolism in a SIRT2-dependent manner, which subsequently activates the p38-MAPK signaling pathway and contributes to nucleus pulposus cell senescence. These findings suggest a functional NAMPT\/SIRT2\/lactate\/p38-MAPK signaling axis that may play a role in intervertebral disc degeneration. However, the clinical relevance of these observations requires validation in larger patient cohorts with appropriate normal controls. Although further in vivo validation and mechanistic details (e.g., direct regulation of SIRT2 activity) are required, this axis may represent a potential therapeutic target for intervening in IDD.<\/jats:p>","DOI":"10.31083\/fbl51724","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:21:51Z","timestamp":1790698911000},"source":"Crossref","is-referenced-by-count":0,"title":["Mechanism of the NAMPT-SIRT2-Lactate Axis in Senescence of Human Nucleus Pulposus Cells"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4712-8656","authenticated-orcid":true,"given":"Wensheng","family":"Zhang","sequence":"first","affiliation":[{"name":"Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, 510378 Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9696-4665","authenticated-orcid":true,"given":"Ling","family":"Mo","sequence":"additional","affiliation":[{"name":"Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, 510378 Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1008-9497","authenticated-orcid":true,"given":"Haiwei","family":"Guo","sequence":"additional","affiliation":[{"name":"Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, 510378 Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8092-5807","authenticated-orcid":true,"given":"Xibing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, 510378 Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9912-4766","authenticated-orcid":true,"given":"Hanwu","family":"Tang","sequence":"additional","affiliation":[{"name":"Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, 510378 Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4344-4595","authenticated-orcid":true,"given":"Wenchao","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, 510378 Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2370-1623","authenticated-orcid":true,"given":"Caijun","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, 510378 Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Knezevic NN, Candido KD, Vlaeyen JWS, Van Zundert J, Cohen SP. 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