{"id":277,"title":"Lactylation of GRP78 regulate Cx43 hemichannel activity to suppress accelerated follicular atresia in premature ovarian insufficiency","title_zh":"GRP78 乳酰化调控 Cx43 半通道活性，抑制早发性卵巢功能不全中加速的卵泡闭锁","url":"https://pubmed.ncbi.nlm.nih.gov/42989310","doi":"10.1186/s12967-026-08737-3","pmid":"42989310","journal":"J Transl Med","kind":"paper","lang":"en","published_at":"2026-08-05T00:00:00+00:00","fetched_at":"2026-11-08T03:44:04+00:00","authors":["Lei S","Xue H","Nong W","Huang Q","Wei Y","Yang J","Cai Y","Dai J","Luo J","Lei X"],"primary_topic":"oocyte","topics":[{"slug":"oocyte","score":10.0,"hits":["follicle","follicular","granulosa","ovarian"]},{"slug":"repro-endo","score":10.0,"hits":["amh","anti-müllerian","estradiol","follicle-stimulating hormone","fsh","poi","premature ovarian insufficiency"]},{"slug":"repro-aging","score":2.0,"hits":["nad+","nicotinamide"]},{"slug":"omics-methods","score":1.0,"hits":["lc-ms"]}],"topic_score":10.0,"preference_score":0.0,"preference_labels":[],"llm_score":79.0,"final_score":79.0,"score_dims":{"novelty":84,"rigor":80,"impact":76,"relevance":88,"translation":72},"recommend_reason":"首次将蛋白乳酰化这一代谢-表观修饰引入 POI 卵泡闭锁机制，靶点（GRP78 K352）与效应分子（Cx43 半通道）明确，证据链从动物表型延伸到位点突变验证，对卵泡生物学与 POI 干预研究有参考价值；但尚限于大鼠模型，NMN/乳酰化轴的临床转化仍需人源与更多功能验证。","keywords":["早发性卵巢功能不全","蛋白乳酰化","GRP78","Cx43 半通道","颗粒细胞凋亡","烟酰胺单核苷酸"],"selected":1,"story_id":467,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"pubmed-endo-genetics","source_name":"PubMed · 生殖内分泌/遗传/保存","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":null,"journal_tier":"unknown","journal_if":null,"is_mock":false,"summary_zh":"该研究以环磷酰胺诱导的 POI 大鼠模型为对象，用 NMN 或雌二醇干预，结合 RNA 测序、Western blot、TUNEL、免疫荧光及活性蛋白质谱（ABPP）、共免疫沉淀、LC-MS/MS 与定点突变等方法，探讨蛋白乳酰化在卵泡闭锁中的作用。结果显示，NMN 通过补充 NAD+ 上调 HK2、PKM2、LDHA，恢复糖酵解与乳酸生成，改善动情周期、激素水平并减少颗粒细胞凋亡与氧化应激；乳酸经 P300 介导在 GRP78 的 K352 位点发生乳酰化，维持 Cx43 表达与半通道活性，K352R 突变则削弱 Cx43 功能并加重凋亡。研究提出乳酸-GRP78 乳酰化-Cx43 轴是 POI 卵泡闭锁的新机制与潜在干预靶点。","summary":"BACKGROUND: Premature ovarian insufficiency (POI) is a refractory reproductive disorderfeatured by accelerated follicular atresia and granulosa cells (GCs) apoptosis, yet the underlying metabolic-epigenetic mechanism remains unclear. This study aimed to explore the role of protein lactylation in follicular atresia during the progression of POI. METHODS: A cyclophosphamide-induced POI rat model was established and treated with nicotinamide mononucleotide (NMN) or estradiol (E2). Estrous cycle, ovarian morphology, reproductive hormone levels and follicle counts were evaluated. RNA-sequencing, qRT-PCR, Western blotting, TUNEL assay and immunofluorescence were used to detect cell apoptosis, glycolysis and related gene expression. Activity-based protein profiling (ABPP), co-immunoprecipitation, LC-MS/MS and site-directed mutagenesis were applied to identify lactate target proteins and lactylation sites. Cx43 hemichannel activity was measured by ethidium bromide uptake assay. Data were analyzed using unpaired t-test or one-way ANOVA followed by Bonferroni's post-hoc test. RESULTS: NMN treatment restored estrous cyclicity, decreased serum follicle-stimulating hormone (FSH) level, increased anti-Müllerian hormone (AMH) and estradiol (E2) levels, and inhibited granulosa cell apoptosis and oxidative stress in POI rats. NMN elevated ovarian NAD+ level, upregulated glycolytic rate-limiting enzymes (HK2, PKM2, LDHA) and restored lactate production. Lactate enhanced Cx43 expression and hemichannel activity. GRP78 was identified as a direct target protein of lactate, which was lactylated at lysine 352(K352) by the acetyltransferase P300. GRP78 lactylation maintained Cx43 expression and lactate transport function, while the K352R mutation impaired Cx43 activity, aggravated granulosa cell apoptosis and oxidative stress. CONCLUSION: NMN promotes glycolysis and lactate production by replenishing NAD+. Lactate-induced GRP78 lactylation at K352 maintains Cx43 function and suppresses follicular atresia. Lactylation of GRP78 provides a novel molecular mechanism and potential therapeutic target for POI.","interpretation_basis":null,"fulltext_status":null,"interpretation":null,"fulltext":{"available":false,"status":null,"reason":"尚未抓取全文（未入选、分数未达阈值，或还没跑 fulltext 步骤）","pmcid":null,"license":null,"chars":0,"source":null,"fetched_at":null}}