Lactate and lactylation: mechanisms, function, diseases, and therapeutic targets.

Within the research landscape of pan-systemic disease mechanisms, the female reproductive system constitutes a core paradigm for studying lactate metabolism and lactylation due to its unparalleled physiological complexity. Distinguishable from the relatively constant biological background of other tissues, this system undergoes recurrent cycles of tissue shedding and regeneration, where such highly dynamic periodic metabolic remodeling provides an exceptional model for observing how lactate functions as a signaling hub to coordinate physiological inflammation and tissue repair. Furthermore, the naturally hyper-lactatemic state and low-pH niche of the reproductive tract microenvironment establish extreme and unique metabolic sensing mechanisms, rendering the role of lactylation in regulating host immune tolerance, embryo implantation, and pathological fibrosis far more representative than in other systems. Additionally, lactylation levels within the reproductive system are directly linked to germ cell quality and the establishment of early epigenetic programs, with its regulatory significance in transgenerational metabolic memory endowing this research with profound implications that transcend individual pathogenesis. Consequently, an in-depth exploration of lactate-driven mechanisms in the female reproductive system not only elucidates the underlying logic of gynecological malignancies and infertility but also provides a decisive scholarly contribution to the global mapping of human diseases regarding the metabolic regulation of complex life-cycle evolution. Ovarian cancer (OC) is the deadliest gynecological malignancy, responsible for an estimated 140,000 deaths worldwide annually. As reported by the International Agency for Research on Cancer in 2020, OC ranked 18th in terms of newly diagnosed cases and 14th in terms of mortality worldwide [ 172 ]. Therefore, elucidating the molecular mechanisms underlying the occurrence and progression of OC is crucial for designing novel therapeutic strategies to improve patient prognosis. The prevalence of aerobic glycolysis in ovarian cancer has been confirmed in both clinical specimens and preclinical models. Compared to early-stage (I/II) cases, late-stage (III/IV) ovarian cancer exhibits significantly elevated levels of glycolytic enzymes, which are often associated with metastasis [ 173 ]. Liu et al. demonstrated a strong correlation between enhanced glycolytic activity and poor prognosis in ovarian cancer patients [ 174 ]. Hexokinase 2 (HK2), a key rate-limiting enzyme in glycolysis, plays a pivotal role in regulating lactate production, promoting ovarian cancer metastasis and stemness through the FAK/ERK1/2 signaling pathway-mediated MMP9/NANOG/SOX9 expression [ 175 ]. The expression of HK2 is regulated by a variety of signaling pathways and transcription factors, such as PI3K/AKT, FAK/ERK1/2, RAS, HIF-1 and STAT2. MiR-145 directly targets and inhibits the expression of HK2, while also indirectly downregulating the levels of PKM2 and LDH, leading to a reduction in glucose utilization and lactate production. DNA methyltransferase 3 A (DNMT3A) enhances glucose uptake and lactate production by upregulating the expression of HK2 and PKM2. As a negative regulator of the Warburg effect induced by DNMT3A in ovarian cancer cells, MiR-145 emerges as a promising therapeutic target for enhancing anticancer treatments [ 176 ]. Phosphofructokinase 1 (PFK1) catalyzes the conversion of fructose-6-phosphate to fructose-1,6-bisphosphate, an irreversible reaction that plays a critical role in controlling the rate and extent of glycolysis. Elevated PFK activity has been linked to poor metastasis and survival rates. Endogenous nitric oxide synthase NOS1 can stabilize PFKM tetramerization by inducing S-nitrosylation at the Cys351 site of PFKM, thus counteracting negative feedback from downstream metabolites, resulting in increased glycolysis and tricarboxylic acid cycle flux [ 177 ]. CXCL14 is a secretory pro-mediator produced by cancer-associated fibroblasts (CAFs), which induces the binding of long non-coding RNA (LINC RNA) 00092 to PFKFB2 to promote ovarian cancer (OC) metastasis [ 178 ]. Pyruvate kinase (PKM), the terminal rate-limiting enzyme in glycolysis, facilitates the conversion of phosphoenolpyruvate to pyruvate, a reaction that is coupled with the production of ATP. Research indicates that PSMD14 promotes the deubiquitination of PKM2, leading to increased dimerization and nuclear translocation, enhancing the transcription of downstream oncogenes, and stimulating the malignant progression of ovarian cancer [ 179 ]. Furthermore, AXL, AKT2, and FSH directly regulate the expression of PKM2, thereby enhancing aerobic glycolysis. This modulation subsequently drives increased cell proliferation, invasion, migration, and resistance to cisplatin in ovarian cancer cells [ 180 – 182 ]. Conversely, CHIP can promote the ubiquitination and degradation of PKM2, downregulating its expression and reducing glycolysis and lactate production [ 183 ]. LDHA is the enzyme catalyzing the final step of the glycolytic pathway, converting pyruvate and NADH to L-lactate and NAD. It has been reported that LDHA is upregulated in ovarian cancer compared to normal tissue [ 184 ]. As a tumor suppressor gene, E3 ubiquitin ligase tripartite motif-containing 3 (TRIM3) directly interacts with LDHA, promoting its ubiquitination and degradation. This process inhibits glycolysis and suppresses lactate production in ovarian cancer cells [ 185 ]. Furthermore, miR-383 regulates the expression of LDHA in ovarian cancer cells, thereby impeding aerobic glycolysis, cell proliferation, and invasion [ 186 ]. When cancer cells grow to form tumor masses, the oxygen concentration decreases at the center, causing cells to become hypoxic and activating hypoxia-inducible factors [ 187 ]. Hypoxia-inducible factors are transcription factors located in the cell nucleus that facilitate cellular adaptation to low-oxygen conditions. These include HIF-1α, HIF-2α, and HIF-3α. In ovarian cancer, HIF-1α is often overexpressed and plays a crucial role in regulating the transcription of multiple target genes, such as erythropoietin, GLUT1, HK2, PFK1, PKM, and VEGF. Through this regulation, HIF-1α enhances glucose uptake and lactate production, contributing to the metabolic reprogramming characteristic of cancer cells. Additionally, lactate has been shown to stabilize HIF-1α in the tumor microenvironment, promoting angiogenesis and immune evasion, thereby further advancing cancer progression through this positive feedback loop. Cryptotanshinone inhibits glucose uptake and lactate production induced by cell glycolysis by suppressing the STAT/SIRT3/HIF-1α signaling pathway, thereby inhibiting cell growth and proliferation induced by cell glycolysis [ 188 ]. The HIF-1α inhibitor EF24 reverses the glycolytic effect in OC by downregulating GLUT-1 expression, resulting in significantly reduced glucose uptake, glycolytic rates, and lactate production. This inhibition suppresses the proliferation, invasion, and metastasis of ovarian cancer cells [ 189 ]. Additionally, c-Myc can synergistically interact with HIF-1 on pyruvate dehydrogenase kinase 1 (PDK1), promoting the conversion of glucose to lactate. Knockdown of fructose-1,6-bisphosphatase 1 (FBP1) significantly reverses the low expression of c-Myc, increasing glucose consumption and lactate production, thereby promoting the progression and cisplatin resistance of ovarian cancer [ 190 ]. The increase in glycolysis not only meets the greater metabolic energy demands of tumors but also leads to acute and chronic acidification of the local environment through the conversion of pyruvate to lactate. This microenvironmental acidosis inhibits gap junction conductivity, thereby suppressing invasion and metastasis, and may activate matrix metalloproteinases that promote extracellular matrix and basement membrane degradation [ 189 , 191 ]. Dong et al. found that lactate can reduce the protein levels and phosphorylation of STAT1 in ovarian cancer cells, thereby inhibiting interferon-α (IFN-α) induced expression of interferon-stimulated genes (ISGs) and ultimately suppressing antitumor activity. They also demonstrated that LDHA knockdown combined with IFN-α treatment effectively enhances the anti-ovarian tumor response, such as increased infiltration and activity of CD8 + T cytotoxic cells and NKT cells, providing new insights for improving the efficacy of IFN-α treatment [ 192 ]. Bandopadhyay et al. found that paired-like homeodomain transcription factor 2 (PITX2) induces protein kinase B (AKT)-mediated glycolysis in ovarian cancer cells. Overexpression of PITX2 promotes the nuclear translocation of LDHA and enhances lactate production. Lactate promotes histone deacetylase (HDAC) inhibition and global histone acetylation. This may ultimately lead to increased proliferation of ovarian cancer cells by upregulating the proliferating cell nuclear antigen (PCNA) and KI67 genes [ 193 ]. Of note, research has found higher levels of MCT1 and MCT4 expression in epithelial ovarian cancer (EOC) cell lines, primary EOC tissues, and metastatic lesions compared to benign and normal ovarian tissues. These transporters play a crucial role in the rapid transport of lactate, essential for the heightened glycolysis in tumor cells. The study also demonstrated that elevated levels of MCT1/MCT4 are associated with tumor grade, clinical stage, residual tumor, and ascites, and are involved in the progression and metastasis of EOC, potentially serving as a target for controlling EOC metastasis [ 194 ] (Fig.  4 ). Fig. 4 Mechanisms of lactate metabolism in ovarian cancer. a . Key rate-limiting enzymes in glycolytic pathways, including HK2, PFK1, PKM, and LDHA, are upregulated in ovarian cancer, promoting glycolysis and lactate production, thus facilitating tumor cell proliferation and invasion. b . Decreased oxygen levels in the tumor core place cancer cells in hypoxic conditions, activating HIF-1α, which is overexpressed and regulates the transcription of various genes, including erythropoietin, GLUT1, HK2, PFK1, PKM, and VEGF, promoting glucose uptake and lactate production. Lactate stabilizes HIF-1α in the stroma, enhancing angiogenesis and immune evasion, forming a positive feedback loop. c . Lactate decreases the levels and phosphorylation of STAT1 protein in ovarian cancer cells, inhibiting IFNα-induced ISG expression and ultimately suppressing antitumor activity. Additionally, lactate promotes HDAC inhibition and overall histone acetylation, ultimately enhancing ovarian cancer cell proliferation by upregulating PCNA and KI67 genes. d. MCT1 and MCT4 facilitate rapid lactate transport in ovarian cancer cells, participating in disease progression Mechanisms of lactate metabolism in ovarian cancer. a . Key rate-limiting enzymes in glycolytic pathways, including HK2, PFK1, PKM, and LDHA, are upregulated in ovarian cancer, promoting glycolysis and lactate production, thus facilitating tumor cell proliferation and invasion. b . Decreased oxygen levels in the tumor core place cancer cells in hypoxic conditions, activating HIF-1α, which is overexpressed and regulates the transcription of various genes, including erythropoietin, GLUT1, HK2, PFK1, PKM, and VEGF, promoting glucose uptake and lactate production. Lactate stabilizes HIF-1α in the stroma, enhancing angiogenesis and immune evasion, forming a positive feedback loop. c . Lactate decreases the levels and phosphorylation of STAT1 protein in ovarian cancer cells, inhibiting IFNα-induced ISG expression and ultimately suppressing antitumor activity. Additionally, lactate promotes HDAC inhibition and overall histone acetylation, ultimately enhancing ovarian cancer cell proliferation by upregulating PCNA and KI67 genes. d. MCT1 and MCT4 facilitate rapid lactate transport in ovarian cancer cells, participating in disease progression Cervical cancer remains a significant global health burden, ranking fourth in both incidence and mortality rates. In 2020, there were 342,000 deaths and 604,000 new cases reported [ 195 ]. As a typical feature of cancer cells, enhanced aerobic glycolysis and increased lactate production exist in cervical cancer, which are significantly associated with tumor recurrence and metastatic potential, ultimately leading to poor patient prognosis. Chen et al. found the NAT10/ac4C/FOXP1 axis as a driver of glycolysis and lactate production in cervical cancer, and the lactate-rich tumor microenvironment (TME) further promotes the immunosuppressive characteristics of tumor-infiltrating regulatory T cells (Tregs) [ 196 ]. Additionally, HPV E6/E7 activates insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) to induce m6A methylation modification of c-Myc mRNA, further promoting aerobic glycolysis, proliferation, and metastasis of cervical cancer [ 197 ]. Beyond its role in histone modifications, non-histone lactylation modification has also been implicated in the occurrence and development of cervical cancer. Meng et al. confirmed that HPV-16 E6 promotes the formation of G6PD dimers and increases its enzyme activity by inhibiting lactylation of the K45 site of glucose-6-phosphate dehydrogenase (G6PD), thereby activating the pentose phosphate pathway (PPP) to promote proliferation of cervical cancer cells [ 88 ]. Furthermore, L-lactate inhibits the degradation of DCBLD1 by directly increasing lactylation modification of DCBLD1, suppressing G6PD autophagic degradation and activating PPP, ultimately promoting cervical cancer progression [ 87 ]. Xiao et al. found that lactate stimulation promotes the translocation of β-catenin from the cytoplasmic membrane to the nucleus, which in turn triggers the redistribution of fascin between the nucleus and cytoplasm, specifically to the protrusion compartment. Moreover, in both in vitro and in vivo murine xenograft models, the application of a lactate antagonist effectively inhibited lactate-induced nuclear import of β-catenin, nuclear export of fascin, and the growth and invasive behavior of cervical cancer cells [ 198 ]. Ciszewski et al. proposed that lactate enhances hydroxycarboxylic acid receptor 1 (HCA1) signaling and induces transcription of DNA repair genes, as well as recruitment of DNA-PKcs, breast cancer susceptibility gene 1 (BRCA1), and nibrin to the nuclear compartment, due to lactate's inhibitory activity on histone deacetylases, leading to chromatin acetylation. The lactate-enriched microenvironment enhances the repair of genomic DNA damage induced by chemotherapy or radiation, thereby promoting the survival of cancer cells. The upregulation of cellular DNA repair mechanisms is a critical factor that contributes to the resistance of cervical cancer to radiotherapy and chemotherapeutic treatments [ 199 ]. Additionally, extracellular lactate supplementation reduces the expression of HPV-16 E6 and E7 oncogenes and promotes migration and invasion of SiHa cervical cancer cells through upregulation of the miR-774/ARHGAP5 axis [ 200 ]. Inhibition of lactate production or transport decreases the expression of M2 macrophage markers in macrophages co-cultured with HPV-positive cell lines, while also enhancing the ability of these macrophages to activate T lymphocytes [ 201 ]. In summary, targeting lactate metabolism may be an effective strategy for anticancer therapy in cervical cancer. Therefore, aberrantly expressed lactate transporters MCTs and GPR81 in cervical cancer merit further investigation. The female lower reproductive tract is characterized by high lactate concentrations, with vaginal secretions containing up to 50 mM of lactate [ 202 ]. In addition to glycolysis, the main source of lactate in the cervical-vaginal environment is derived from lactobacilli. Lactobacilli promote cervical-vaginal health by producing lactate and other antibacterial compounds. Lactate effectively lowers local pH and creates an unfavorable environment for pathogens, thereby preventing pathogenic diseases such as urinary tract infections, sexually transmitted infections, and bacterial vaginosis [ 203 ]. The lactate subtypes secreted by Lactobacillus species such as L. crispatus, L. gasseri, and L. jensenii are protective factors against HPV infection and cervical lesions [ 204 ]. Numerous studies indicate a close correlation between the absence of lactobacilli in the female reproductive tract and persistent high-risk HPV infection and tumor progression. However, Colbert et al. discovered that inert lactobacilli, such as L. iners, in the tumor microenvironment may have a symbiotic relationship with cancer cells. L. iners, a facultative anaerobe, can generate ATP through aerobic respiration and efficiently produce lactate under anaerobic conditions. It has been linked to reduced patient survival, the induction of chemoradiotherapy resistance in cervical cancer cells, and the reprogramming or alteration of various metabolic pathways within tumors [ 205 ] (Fig.  5 ). Fig. 5 Mechanisms of lactate metabolism in cervical cancer. a . PPP and glycolytic pathway are upregulated in cervical cancer, promoting tumor progression. b . Upregulated lactate in tumor cells accelerates the repair of genomic DNA damaged by anticancer drugs/radiation, promoting cancer cell survival. Lactate decreases the expression of HPV-16 E6 and E7 oncogenes, but simultaneously promotes the migration and invasion of cervical cancer cells by upregulating the miR-774/ARHGAP5 axis. Moreover, inhibition of lactate synthesis or transport improves the activation potential of T lymphocytes in macrophages. c . Lactate in the cervical-vaginal environment is primarily produced by lactobacilli, which lowers the local pH and creates an inhospitable environment for pathogens, thereby helping to prevent infectious diseases Mechanisms of lactate metabolism in cervical cancer. a . PPP and glycolytic pathway are upregulated in cervical cancer, promoting tumor progression. b . Upregulated lactate in tumor cells accelerates the repair of genomic DNA damaged by anticancer drugs/radiation, promoting cancer cell survival. Lactate decreases the expression of HPV-16 E6 and E7 oncogenes, but simultaneously promotes the migration and invasion of cervical cancer cells by upregulating the miR-774/ARHGAP5 axis. Moreover, inhibition of lactate synthesis or transport improves the activation potential of T lymphocytes in macrophages. c . Lactate in the cervical-vaginal environment is primarily produced by lactobacilli, which lowers the local pH and creates an inhospitable environment for pathogens, thereby helping to prevent infectious diseases Endometrial cancer (EC) is the sixth most common cancer in women and one of the three most common malignancies in gynecology. Its incidence has been steadily increasing worldwide [ 206 ]. Elevated lactate levels in both serum and lesion tissues of endometrial cancer patients have been confirmed by multiple studies, consistent with the higher glycolytic rate in cancer cell metabolism [ 207 , 208 ]. Wang et al. demonstrated that small nucleolar RNA host gene 9 (SNHG9) directly increases the expression of HK2, which subsequently activates the FAK/ERK1/2 signaling pathway. This activation promotes aerobic glycolysis in endometrial cancer cells, driving cell proliferation and facilitating invasive growth via epithelial-mesenchymal transition (EMT) [ 209 ]. The elevated expression of PKM2 is strongly linked to poor prognosis in endometrial cancer. Estrogen induces the upregulation of PKM expression through the c-Myc/hnRNP splicing pathway, facilitating the formation of PKM2. This results in the disruption of its tetrameric structure and triggers its translocation to the nucleus, thereby promoting the Warburg effect [ 210 ]. Gong et al. identified that anterior gradient 2 (AGR2) interacts with MUC1 to stimulate the expression of HIF-1α. In turn, HIF-1α regulates key proteins such as LDHA, HK2, ENO1, and PGK1, driving a metabolic shift from oxidative phosphorylation to glycolysis. This shift results in increased lactate production, enhanced vascularization, and the promotion of an invasive phenotype in endometrial cancer [ 211 ]. Additionally, kinesin family member 23 (KIF23) is upregulated under hypoxic conditions in a HIF-1α-dependent manner and participates in lactate metabolism in uterine corpus endometrial carcinoma (UCEC) by regulating LDHA expression [ 212 ]. Shi et al. constructed a prognostic model based on lactate metabolism-related genes (LMRGs) and further identified translocase of inner mitochondrial membrane 50 (TIMM50) as a key potential prognostic marker for EC. Experimental evidence confirmed that TIMM50 promotes proliferation, migration, and lactate generation in EC cells [ 213 ]. Many studies have confirmed the enhanced glycolytic activity in EC, creating favorable conditions for cancer cell proliferation, invasion, and migration, along with a concurrent increase in lactate, the primary product of glycolysis [ 214 – 217 ] While the mechanisms underlying lactate's actions in EC remain to be fully elucidated. Recent research has revealed that excess lactate produced in EC stimulates lactylation of histone H3 lysine 18, regulating the expression of ubiquitin-specific peptidase 39 (USP39). USP39, through interaction with PGK1, activates the PI3K/AKT/HIF-1α signaling pathway, thereby stimulating glycolysis to produce more lactate, further increasing histone lactylation. This positive feedback loop further promotes the growth and metastasis of EC [ 89 ]. Given the critical involvement of lactate in tumor initiation and progression, targeting lactate metabolism offers a promising strategy for further research and potential therapeutic interventions in endometrial cancer (Fig.  6 ). Fig. 6 Mechanisms of lactate metabolism in endometrial cancer. a . SNHG9 directly upregulates HK2 expression, leading to HK2 overexpression of FAK and its downstream ERK1/2 signaling pathways, enhancing cell migration, invasion, and stemness regulation in tumor cells. b . Estradiol upregulates PKM expression via c-Myc/hnRNP, promoting the formation of PKM2, which disrupts its tetrameric structure and promotes nuclear translocation, thereby inducing the Warburg effect. c . AGR2 interacts with MUC1 to activate the expression of HIF-1α, which in turn regulates critical glycolytic enzymes such as ALDH, HK2, ENO1, and PGK1. This shift from oxidative phosphorylation to glycolysis enhances lactate production, while simultaneously promoting angiogenesis and the development of invasive phenotypes. d . Lactate stimulates lactylation of histone H3 at lysine 18 in endometrial cancer, promoting interaction, stabilization, and deubiquitination of USP39 and PGK1, thereby activating the PI3K/AKT/HIF-1α signaling pathway, stimulating glycolysis and producing more lactate, creating a positive feedback loop Mechanisms of lactate metabolism in endometrial cancer. a . SNHG9 directly upregulates HK2 expression, leading to HK2 overexpression of FAK and its downstream ERK1/2 signaling pathways, enhancing cell migration, invasion, and stemness regulation in tumor cells. b . Estradiol upregulates PKM expression via c-Myc/hnRNP, promoting the formation of PKM2, which disrupts its tetrameric structure and promotes nuclear translocation, thereby inducing the Warburg effect. c . AGR2 interacts with MUC1 to activate the expression of HIF-1α, which in turn regulates critical glycolytic enzymes such as ALDH, HK2, ENO1, and PGK1. This shift from oxidative phosphorylation to glycolysis enhances lactate production, while simultaneously promoting angiogenesis and the development of invasive phenotypes. d . Lactate stimulates lactylation of histone H3 at lysine 18 in endometrial cancer, promoting interaction, stabilization, and deubiquitination of USP39 and PGK1, thereby activating the PI3K/AKT/HIF-1α signaling pathway, stimulating glycolysis and producing more lactate, creating a positive feedback loop Endometriosis and adenomyosis are two distinct but related gynecological disorders marked by the presence of endometrial-like tissue outside its normal location. In endometriosis, this tissue grows outside the uterus, whereas in adenomyosis, it is found within the muscle layer of the uterus. Both conditions are associated with symptoms such as pelvic pain, abnormal bleeding, and fertility issues [ 218 ]. The etiology of endometriosis remains unknown, but it shares similar characteristics with tumors, such as abnormal glucose metabolism, indicating potential metabolic dysregulation [ 219 ]. Numerous glycolytic enzymes, such as 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), are highly expressed in endometriosis cells, contributing to the progression of endometriosis [ 220 ]. Proviral insertion in murine lymphomas 2 (PIM2) promotes glucose consumption, lactate production, and the expression of glycolytic enzymes by increasing PKM2 expression, leading to fibrosis in endometriosis. Carboxyl terminus of Hsc70-interacting protein (CHIP) serves as a novel HMGB1 binding protein, targeting the ubiquitination and degradation of glycolysis-associated gene HMGB1, thereby inhibiting the proliferation and invasion of endometriosis [ 221 ]. Several glycolysis-related genes, such as HIF-1α, TGF-β, GLUT, PDK1, HK2, LDHA and PKM2, are highly expressed in endometriotic cells, promoting the development of endometriosis [ 222 ]. The differential expression of glycolysis-related genes in endometriosis tissue-derived cells leads to changes in glucose consumption and lactate production, which may be associated with inflammatory responses, hormonal changes, immune alterations, decreased oxygen tension, and elevated levels of free iron, all of which contribute to the pathogenesis of endometriosis [ 223 ]. Lactate, as a metabolic byproduct of glycolysis, increases cell migration, invasion, angiogenesis, and immune evasion during tumorigenesis, all of which are associated with the development of endometriosis. Therefore, the increased levels of lactate may contribute to the survival and establishment of endometriotic lesions, akin to the mechanism observed in cancer cell metastasis. Studies have confirmed a significant increase in lactate levels in peritoneal fluid from women with endometriosis and in stromal cells isolated from endometrial tissues. This elevated lactate production may provide energy for endometriotic cells, facilitating their survival, implantation, and invasion into the peritoneum, thereby contributing to the pathogenesis of endometriosis [ 223 , 224 ]. Guo et al. discovered that lactate drives M2 polarization of macrophages in endometriotic lesions through the Mettl3/Trib1/ERK/STAT3 signaling pathway. This polarization results in immune-suppressive characteristics due to the abnormal secretion of chemokines and decreased phagocytic ability of macrophages [ 225 ]. Recent studies have explored the role of lactate-induced histone lactylation in the pathogenesis of endometriosis. Elevated levels of lactate and LDHA in endometriotic lesions enhance H3K18 lactylation in ectopic endometrial tissue and eutopic endometrial stromal cells (eESCs), promoting cell proliferation, migration, and in vitro invasion of endometriosis through upregulation of HMGB1 [ 226 ]. High expression of the lncRNA H19 in endometriosis promotes aerobic glycolysis and histone acetylation, thereby enhancing the proliferation and migration capacity of human endometrial stromal cells (HESCs) [ 227 ]. Metabolomic studies of follicular fluid in patients with endometriosis have shown elevated levels of pyruvate, lactate and glucose [ 228 , 229 ]. This is interpreted as alterations in cellular glycolysis in follicular fluid associated with endometriosis due to the inflammatory processes during the disease. Enhanced anaerobic glycolysis in oocytes and granulosa cells is observed. As oocytes lack glucose transporters, they obtain energy from granulosa cells via lactate and pyruvate through gap junctions. Therefore, changes in the metabolic pattern of endometriotic granulosa cells directly impact oocyte development. Studies have shown mitochondrial dysfunction in granulosa cells of endometriosis patients, leading to decreased steroidogenesis, fertilization rates, oocyte maturation rates and oocyte quality [ 230 ]. To compensate for the energy metabolic defects caused by mitochondrial damage, granulosa cells tend to consume glucose through the glycolytic pathway, leading to increased glucose uptake and lactate accumulation. Unlike the pathogenic increase in glycolysis observed in endometriotic endometrial stromal cells, the increased glycolytic activity in granulosa cells can compensate for the energy shortage caused by mitochondrial dysfunction, thereby protecting granulosa cells from premature apoptosis. This adaptive change serves as a protective mechanism for female reproductive capacity [ 231 ]. Adenomyosis is a chronic gynecological condition with a wide-ranging prevalence, estimated between 8 to 62%, often coexisting with other pathologies such as uterine fibroids or endometriosis. It is typically characterized by abnormal uterine bleeding, dysmenorrhea, and infertility, negatively impacting the fertility, pregnancy outcomes, and quality of life of affected individuals [ 232 ]. Research has found that in women with adenomyosis, the expression of HK1, PFKFB3, GAPDH and PDHA mRNA in the ectopic uterine muscle layer is higher compared to the normal uterine muscle layer of women without adenomyosis. This indicates an increase in glycolysis and lactate accumulation in the ectopic uterine muscle layer of women with adenomyosis, which may lead to the infiltration of the endometrium into the uterine muscle layer and promote the development of adenomyosis [ 233 ]. Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder that is marked by increased androgen levels and ovarian dysfunction. It affects approximately 8%−13% of women of reproductive age and is a leading cause of infertility. A hallmark of PCOS is insulin resistance (IR), which is frequently accompanied by compensatory hyperinsulinemia, affecting 50%−70% of women with the condition [ 234 ]. Insulin resistance refers to a diminished capacity of insulin to effectively regulate glucose uptake and production within the body. This condition can lead to downregulation of PI3K expression, thereby inhibiting the PI3K/AKT signaling pathway. As a result, the insulin-mediated regulation of glucose metabolism is impaired, disrupting the local glucose metabolism in the ovaries [ 235 , 236 ]. Insulin controls the expression of GLUTs in granulosa cells, thereby regulating the uptake of glucose by oocytes and granulosa cells, leading to the accumulation of glucose in the local compartment (i.e., follicular fluid) [ 237 ]. In PCOS rats, there is a notable upregulation of GLUT1 expression in the ovaries, while the levels of key glycolytic enzymes, including HK and PFK, are significantly reduced. This suggests a diminished glucose utilization capacity in these animals. Furthermore, the expression of monocarboxylate transporters MCT2 and MCT4 is downregulated, leading to a decreased rate of transport for acetate and lactate [ 238 ]. Moreover, elevated androgens can inhibit the expression of LDHA, reducing lactate production. Crucially, elevated levels of nerve growth factor in the follicular fluid of PCOS patients lead to a significant reduction in the expression of LDHA. This impairment disrupts the communication between granulosa cells and oocytes, ultimately diminishing the developmental potential of the oocytes [ 239 ]. During follicular development, glycolytic activity increases, leading to higher lactate production as follicle diameter enlarges. However, studies have shown reduced lactate concentrations in the follicular fluid of PCOS patients, likely due to decreased glucose uptake and dysregulated LDH activity, which controls the conversion of pyruvate to lactate [ 240 ]. Follicular development in PCOS patients appears to require high lactate concentrations, and increasing lactate levels in follicular fluid in vitro may reduce the occurrence of follicular arrest [ 241 , 242 ]. Research indicates that moderate insulin levels can promote lactate production in the follicular fluid of healthy individuals, but this effect is not significant in PCOS patients. High insulin doses, however, inhibit ovarian granulosa cells (KGN cells) and reduce lactate levels in these cells [ 243 ]. In PCOS, extracellular vesicle-derived microRNAs (miR-143-3p and miR-155-5p) silence glycolysis in KGN cells, lowering lactate production and weakening the environmental stimulus necessary for follicular development [ 244 ]. Recent studies have focused on targeting glycolysis and lactate metabolism abnormalities in PCOS to improve follicular development. Resveratrol (3,4,5-trihydroxy-trans-stilbene, RES) enhances ovarian insulin sensitivity, promotes granulosa cell glycolytic activity, and ameliorates the mechanism of follicular development impairment in PCOS rats. SIRT2 has been identified as a key regulator of RES-mediated glycolysis in ovarian granulosa cells [ 245 ]. Metformin treatment increases LDHA expression in the endometrial tissue of PCOS patients, reversing impaired uterine metabolism by inducing glycolysis and mitochondria-mediated cell death in the proliferative endometrium, which benefits both systemic and local uterine function [ 246 ]. The combination of Diane-35 (2 mg cyproterone acetate and 35 μg ethinylestradiol) with metformin improves glucose metabolism, reduces insulin resistance, lowers serum testosterone, and restores ovulation in PCOS patients. This therapeutic effect may be linked to the regulation of glycolysis-related mediators such as PKM2, LDHA, and SIRT1 [ 238 ]. Implantation is a complex, multi-stage process involving embryo attachment, adhesion, and invasion into the appropriately prepared or "receptive" endometrium of the uterus. Proper embryo implantation into the maternal endometrium is crucial for establishing and developing a healthy placenta and ensuring a successful pregnancy. Studies indicated that approximately 30% of pregnancies end in miscarriage during the peri-implantation period in natural cycles; meaning a significant portion of naturally conceived human pregnancies fails to initiate, complete implantation, and achieve sustained pregnancy [ 247 ]. Before and after implantation, the blastocyst releases substantial amounts of lactate into the surrounding microenvironment. Blastocysts exhibit high levels of aerobic glycolysis, generating large quantities of lactate in the presence of oxygen. In addition to providing energy for blastocyst expansion and mitotic division, this high level of glucose utilization can synthesize triacylglycerols and phospholipids for new membrane synthesis, as well as serve as precursors for complex sugars such as glycoproteins and mucopolysaccharides. Furthermore, the oxygen concentration in the uterine cavity (1.5%−5.3%) is much lower than atmospheric levels (∼20%), and the oxygen availability during implantation, when the embryo invades the endometrium, is limited. Due to the absence of a maternal vascular system, the implantation site is relatively hypoxic. Under conditions of amino acid and carbohydrate metabolism, studies have found that lower oxygen concentrations are associated with upregulation of glucose metabolism and high levels of lactate formation [ 248 ]. In the late blastocyst and early implantation stages, the LDH isoform switches from LDHB (favoring pyruvate formation) to LDHA (favoring lactate formation) [ 249 ]. The high lactate microenvironment created by the blastocyst enables endometrial breakdown, angiogenesis, and immune modulation, facilitating successful implantation. Implantation involves the degradation of the endometrial stroma, which facilitate the invasion of the underlying nutritive layer. Lactate production creates an acidic environment that enhances matrix metalloproteinase (MMP) activity and promotes the production of TGF-β. The resulting low pH reduces tissue inhibitors of metalloproteinases (TIMPs), increasing matrix degradation, and also activates tissue plasminogen activator (tPA) [ 250 ]. Lactate further stimulates hyaluronic acid synthesis, which aids in cell motility. These processes collectively support the invasion and implantation of the nutritive layer. After implantation, the establishment of maternal blood supply to the placenta requires angiogenesis, a process in which lactate plays a direct role. Elevated lactate levels prompt cellular uptake of lactate, activating growth factor pathways. Similarly, implanted embryos release lactate, which is absorbed by surrounding tissues. During implantation, the uterus produces high levels of VEGF in response to lactate stimulation, facilitating vasodilation, endothelial cell proliferation, migration, and ultimately, the formation of blood vessels [ 251 ]. Lactate from the blastocyst, through feedback loops, directly impacts uterine remodeling, immune regulation, and blastocyst function, including its survival via the NFκB pathway [ 252 ]. Preventing maternal rejection of the embryo is critical during implantation. Lactate modulates local immune responses during embryo growth and invasion, significantly reducing the proliferation and expression of T cell receptors and the production of cytokines by cytotoxic T cells. This suppression reduces the local immune response at the implantation site [ 253 ]. Additionally, lactate produced by the embryo can induce VEGF expression in macrophages, further promoting the implantation process [ 254 ]. Therefore, lactate serves as a crucial signaling molecule derived from the embryo, essential for successful implantation. Further research on the role of lactate in endometrial receptivity could improve our understanding of implantation failure, offering new opportunities to enhance the success rates of both natural and assisted pregnancy.

Given the critical role of lactate in pathophysiological processes, lactate-targeted therapies have the potential to inhibit tumor growth and metastasis, as well as to treat inflammation-associated diseases. Currently developed clinical drugs targeting lactate metabolism primarily concentrate on (1) targeting glycolysis within cells, (2) targeting lactate transport, and (3) introducing exogenous substances to consume lactate. Additionally, lactylation modifications play a crucial role in metabolic reprogramming, immune regulation, and various physiological processes, underscoring its pivotal role in disease therapy and its potential as a critical target in epigenetics for disease intervention (Table  2 ). Table 2 Therapeutic agents targeting lactate production, transport, and lactylation modifications Targets Drugs Disease Mechanism Reference LDHA Oxamate Cervical cancer Lactate production [ 271 ] LDHA JQ1 Ovarian cancer Lactate production [ 272 ] LDHA water-extracted P. vulgaris Endometriosis Lactate production [ 276 ] LDHA GSK2837808A Melanoma Lactate production [ 287 ] LDHA NHI-Glc-2 NSCLC and gastric cancer Lactate production [ 288 ] LDHA GNE-140 Pancreatic cancer Lactate production [ 289 ] LDHA/B MS6105 Pancreatic cancer Lactate production [ 290 ] LDHA/B NCI-006 Pancreatic cancer Lactate production [ 291 ] MCT1/2 AR-C155858 (SR13801) Breast cancers, B-cell lymphoma Lactate production [ 292 ] MCT1 AZ3965 CRC, melanoma Lactate excretion [ 293 ] MCT4 ALK-04 Melanoma Lactate excretion [ 294 ] MCT4 α-CHCA Ovarian cancer Lactate excretion [ 279 ] MCT1, MCT4 Atorvastatin, resveratrol endometriosis Lactate excretion [ 280 ] Lactate LOx Breast cancer, Lactate catabolism [ 295 ] Lactate CoMnFe-LDO UM Lactate catabolism [ 296 ] HK2, PFKFB3 Meclizine Adenomyosis Glucose uptake [ 297 ] HK2, PDK1 Sodium selenite Cervical cancer Glucose uptake [ 298 ] LDHA, HK2, PKM2 Cryptotanshinone Ovarian cancer Lactate production, Glucose uptake [ 188 ] LDHA, HK2, PKM2 Ginsenoside F2 Cervical Cancer Lactate production, Glucose uptake [ 299 ] LDHA, HK2, PKM2 Dendrobium nobile-derived polysaccharides PCOS Lactate production, Glucose uptake [ 300 ] Lactylation K673-pe Colorectal cancer Non-histone modification [ 301 ] Lactylation MG149 Colorectal cancer Non-histone modification [ 302 ] Lactylation D34-919 Glioblastoma Non-histone modification [ 84 ] Lactylation RJA Hepatocellular carcinoma Histone modification [ 303 ] Therapeutic agents targeting lactate production, transport, and lactylation modifications LDHA catalyzes the formation of lactate from pyruvate, and inhibiting LDHA can suppress the Warburg effect, shifting the environment to one characterized by high glucose but low lactate levels, thereby controlling cancer progression. This strategy represents a primary target in disease therapy focused on lactate metabolism. Research indicates that LDHA inhibition can increase the sensitivity of drug-resistant cancers to other chemotherapy treatments [ 269 ]. Xiang et al. found that oxamate, a specific LDHA inhibitor, significantly enhances the inhibitory effect of PARP inhibitors on wild-type BRCA ovarian cancer [ 270 ]. In addition, Oxamate also significantly inhibits proliferation of cervical cancer cell lines [ 271 ]. JQ1, a selective small-molecule inhibitor of BET bromodomain proteins, has been found to reduce LDHA activity, inhibit lactate production, decrease energy supply to ovarian cancer cells, and inhibit tumor cell proliferation [ 272 ]. LDHA is considered a feasible target for drug design and discovery, with several small molecules showing significant LDHA inhibition and anticancer activity. However, to date, no reliable LDHA-specific inhibitors have been approved for clinical use to date. Mofetil (also known as AT-101), which targets and inhibits LDHA, is currently in preclinical trials for brain and central nervous system tumors, B-cell non-Hodgkin lymphoma, and other diseases, potentially becoming a future treatment option [ 273 , 274 ]. In addition to LDHA, targeting other rate-limiting enzymes in glycolysis, such as PDH, HK2, 3PFKFB3 and PKM2, as well as glycolysis-related pathways, can effectively reduce lactate production in cells. Cryptotanshinone has been shown to decrease the expression of overactive glycolysis-related enzymes LDHA, HK2, and PKM2, and inhibit the STAT/SIRT3/HIF-1α signaling pathway, thereby suppressing glycolysis in ovarian cancer cells, inhibiting tumor cell growth, and inducing tumor cell apoptosis [ 188 ]. Targeting glycolysis has also been shown to combat drug-resistant diseases. The PFKFB3 inhibitor 3PO can be combined with cisplatin or paclitaxel to enhance the anti-proliferative effects of these chemotherapy drugs in ovarian cancer cells [ 275 ]. Water-extracted Prunella vulgaris significantly inhibits the expression of PDK1/3 and phosphorylation of PDHA, thereby suppressing aerobic glycolysis, inducing apoptosis, and reducing endometriosis lesions [ 276 ]. In patients with endometrial hyperplasia and PCOS, metformin treatment has been shown to normalize the abnormal expression of glycolytic enzymes and mitochondrial-associated proteins, leading to an improvement in endometrial receptivity [ 246 ]. Additionally, due to the downregulation of glycolytic pathway rate-limiting enzymes in PCOS patients, there is a decrease in ovarian glycolytic rates, requiring higher levels of pyruvate and lactate for normal follicular development. Administration of Resveratrol (3,4,5-trihydroxy-trans-stilbene, RES) and Mogroside V significantly upregulates the expression of these glycolytic rate-limiting enzymes. This action restores ovarian glycolytic activity, thereby improving disturbances in ovarian energy metabolism [ 245 , 277 ]. Diane-35 (composed of 2 mg cyproterone acetate and 35 μg ethinyl estradiol) combined with metformin therapy is widely used in clinical treatment for PCOS. It has been demonstrated to upregulate glycolytic rate-limiting enzymes, thereby increasing ovarian lactate levels and improving follicular energy supply [ 238 ]. Furthermore, the glycolysis inhibitor 2-deoxy-D-glucose (2-DG), which competes with glucose, reduces lactate levels in vivo. Phase I clinical trials have demonstrated its clinical efficacy in various solid tumor patients, making it a promising candidate for clinical use [ 278 ]. MCTs are responsible for the transport of lactate in and out of cells. Therefore, MCT inhibitors can influence lactate metabolism and disease progression. For instance, blocking MCT4 with alpha-cyano-4-hydroxycinnamic acid (α-CHCA) disrupts lactate export in ovarian cancer cells, leading to decreased extracellular lactate levels. This shift reverses the epithelial-to-mesenchymal transition in ovarian cancer cells, inhibiting migration [ 279 ]. Atorvastatin and resveratrol significantly reduce MCT1 and MCT4 expression in ectopic endometrial tissues in rats, leading to decreased lesion size and reduced vascularization [ 280 ]. Studies have shown that knocking down MCT1 inhibits cancer cell proliferation and migration, thereby suppressing tumor progression [ 281 ]. Several MCT inhibitors with clinical potential are currently in preclinical trials, including AZD3965 (a pyrrolidine derivative targeting MCT1), fluvastatin (targeting MCT4), and diclofenac (targeting both MCT1 and MCT4). Another therapeutic approach targeting lactate metabolism involves introducing exogenous substances to consume the produced lactate. Lactate oxidase (LOx) catalyzes the conversion of lactate to pyruvate without requiring a coenzyme, making it a naturally occurring enzyme with catalytic activity even higher than endogenous LDH. LOx, derived from various bacteria, holds significant therapeutic potential due to its irreversible lactate consumption. However, the challenge of achieving precise LOx delivery to lesions remains, as systemic administration can cause drug toxicity. To address this, various drug delivery systems, particularly nanomaterials, have been developed. Researchers have encapsulated LOx in nanocapsule, enabling precise and efficient delivery of LOx, enhancing its stability, and reducing systemic drug toxicity [ 282 ]. Additionally, some nanomaterials exhibit LDH-like activity, catalyzing lactate conversion, which holds significant research potential [ 283 , 284 ]. The discovery of lactylation has further expanded the therapeutic strategies related to lactate metabolism. Given its critical role in disease pathogenesis, treatments targeting lactylation are promising and warrant further investigation. The p300/CBP proteins regulate lactylation levels, and inhibitors of p300, such as C646, CCS147, and EP3160, have been shown to reduce lactylation modifications of both histone and non-histone proteins. Although these inhibitors are still in clinical trial phases, they hold promise as potential therapeutic options. Additionally, various compounds have been demonstrated to lower lactylation levels. For instance, the triterpenoid anti-tumor compound demethylzeylasteral inhibits H3K9la and H3K56la lactylation [ 285 ]. Evodiamine has been shown to inhibit lactate-induced lactylation at the H3K18la site [ 286 ]. However, the specific targets of these compounds are still undetermined, and underlying mechanisms and additional compounds targeting lactylation sites warrant further exploration.

In this review, we summarize the pathways and mechanisms of lactate production and clearance, as well as the biological functions of lactate metabolism. We further discuss the historical development of lactate research, the potential of lactate metabolism as a diagnostic and prognostic biomarker, and its promising prospects as a therapeutic target. As a major product of glycolysis, lactate has increasingly been recognized for its multifaceted roles in both physiological and pathological processes, including energy metabolism, immune regulation, and signal transduction. The functions of lactate are inherently dualistic: it can promote immune evasion, yet some studies report beneficial effects on T cell function. Similarly, lactate can amplify inflammatory responses while also facilitating inflammation resolution. The paradoxical roles of lactate in disease warrant further investigation; however, for tumor- and inflammation-related disorders, therapeutic strategies primarily focus on promoting lactate clearance and inhibiting lactate production [ 198 ]. This duality complicates lactate-targeted therapies. In conditions such as PCOS, where ovarian lactate levels are reduced and energy metabolism is dysregulated, leading to impaired follicular development, supplementation of ovarian lactate represents a more appropriate intervention [ 245 ]. Nonetheless, challenges remain: would increasing lactate levels adversely affect tissues beyond the follicular microenvironment, and would lactate-lowering treatments for inflammatory diseases of the female reproductive system impact fertility in women of childbearing age? In cardiomyocytes, α-MHC-K1897la stabilizes sarcomeres and enhances contraction, whereas H3K18la primarily drives pathological hypertrophy, indicating that simple lactate supplementation or reduction may not provide an optimal solution. Accordingly, developing more precise and effective delivery strategies that selectively target specific lactate metabolic pathways and tissue sites is especially important. Nanomedicine-based targeted delivery of lactate metabolic modulators offers a safer and more reliable approach to minimize systemic toxicity. Current research has demonstrated promising progress in delivering modulators of MCTs, glycolytic rate-limiting enzymes, and LOX, highlighting their potential as therapeutic targets [ 282 ]. With the emerging focus on lactylation, our understanding of lactate's functions has reached new heights. Enzymes and genes associated with lactylation could become novel therapeutic targets beyond lactate metabolism pathways [ 39 ]. Nevertheless, several intriguing scientific questions remain to be addressed. First, although numerous studies have demonstrated dynamic changes in lactate levels across various disease processes, the temporal dynamics of these changes during disease progression remain poorly understood. Future research should employ multidimensional approaches, integrating spatial metabolomics, single-cell epigenomics, and functional validation, to delineate the precise roles of lactylation in disease pathogenesis. Second, the complete lactylation landscape remains unresolved in many diseases. Third, the specific mechanistic contributions of differentially expressed histone and non-histone lactylation to disease pathogenesis require further investigation. Beyond the established roles in enhancing protein expression, promoting nuclear gene accessibility, and stabilizing gene expression in other contexts, additional mechanisms may be involved. Finally, current research on lactylation primarily focuses on competitive inhibitors of p300/CBP, while specific lactylation “erasers” remain elusive. Therefore, the development of more targeted lactylation-modulating therapeutics represents a highly anticipated strategy for clinical intervention. The critical roles of lactate metabolism-related genes in the progression of various diseases have also opened new avenues for disease diagnosis and prognostic assessment. Studies have shown that serum lactate dehydrogenase (LDH) levels are abnormally elevated in certain pathological conditions, highlighting the potential of lactate metabolism-related genes as non-invasive diagnostic biomarkers [ 304 ]. However, given lactate's involvement in numerous complex physiological processes, overly simplistic interpretations of lactate metabolism-related indicators could lead to significant misconceptions. A more nuanced understanding of lactate levels and their diverse functions, combined with the assessment of additional indicators, is required to improve the clinical relevance of these diagnostic and prognostic markers. Lactate and its metabolic processes play a pivotal role in the initiation and progression of various diseases. Aberrations in lactate production, transport, and lactylation are key contributors to disease pathogenesis, while lactate levels can serve as valuable diagnostic and prognostic biomarkers. Strategies aimed at modulating lactate production and transport, regulating circulating lactate concentrations, and manipulating epigenetic modifications such as lactate-induced lactylation may offer innovative approaches for disease therapy.

Metabolic reprogramming refers to the cellular adaptation to changes in the microenvironment by adjusting the redistribution of glucose, lipids and amino acids to meet increased energy and biosynthetic demands [ 1 ]. In inflammatory-related diseases, the proliferation of inflammatory cells forms a malignant inflammatory microenvironment, prompting cells to undergo metabolic reprogramming, altering the energy supply mode of cells within the microenvironment, thus influencing the progression of the disease [ 2 ]. Even under aerobic conditions, abnormally proliferating cells preferentially convert glucose into pyruvate to produce lactate, accompanied by limited adenosine triphosphate (ATP) generation, a process known as aerobic glycolysis. This low-energy metabolic pathway was first observed by Otto Warburg and is therefore also referred to as the "Warburg effect" [ 3 ]. The Warburg effect is prominently associated with diverse pathophysiological processes involving oncogenesis and inflammation [ 4 – 7 ]. The accumulation of lactate, regulated by numerous key enzymes, is the endpoint of the Warburg effect. Lactate was previously regarded as a major fatigue agent or metabolic toxin primarily derived from glycolysis, acutely accumulating during exercise and chronically in tumor microenvironments (TME) and inflammatory sites. Since the lactate revolution of the 1970 s, lactate has been repositioned as a distinctive energy source and crucial signaling molecule, recognized as a major metabolic intermediate. Recent studies have found that it can mediate immune-inflammatory responses, angiogenesis, fibrosis, and other processes [ 4 ]. As a pro-angiogenic factor, lactate promotes angiogenesis by stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing vascular endothelial growth factor (VEGF) expression [ 5 ]. Moreover, lactate has the ability to both directly and indirectly suppress anti-tumor responses. Research has shown that lactate-induced HIF-1α can drive the differentiation of myeloid-derived suppressor cells (MDSCs) into tumor-associated macrophages (TAMs) by modulating the expression of inducible nitric oxide synthase (iNOS) and arginase-1 (ARG1), thereby promoting the suppression of adaptive immune responses [ 6 , 7 ]. Three major milestones have shaped lactate metabolism research: the discovery of the "Warburg effect" by Otto Warburg in 1921, George Brooks' proposal of the "lactate shuttle theory" in 1984, and the 2019 discovery by Yingming Zhao's team of lactylation, a novel post-translational modification (PTM) that modifies histones and functional proteins, providing new insights into gene regulation and expression [ 8 – 10 ]. Building upon these milestones, it is now evident that lactate acts as a vital intermediary, translating metabolic signals into stable cellular programs via lysine lactylation. This review systematically delineates how lactylation bridges metabolic reprogramming and multisystemic pathogenesis, driving diverse conditions such as tissue fibrosis, neuroinflammation, and autoimmune dysfunction across various organ systems. Notably, we highlight the female reproductive tract as a core physiological model, given its naturally acidic niche and high-intensity metabolic flux. By integrating metabolic mechanisms and immune crosstalk, we detail how lactylation orchestrates the progression of major gynecological pathologies and critical reproductive processes. Ultimately, this framework underscores the significant regulatory roles of lactate and lactylation in cellular biology, positioning them as promising pharmacological targets for precision medicine.