Research report: Mechanistic insights into lactate-driven pathogenesis in diabetic kidney disease

A structured narrative review concludes that lactate may help connect metabolic reprogramming, epigenetic remodeling and immune inflammation in diabetic kidney disease, a complication affecting an estimated 25%–40% of people with diabetes and remaining a leading cause of end-stage renal disease worldwide. The authors distinguish lactate’s proposed role as an active signaling molecule from its better-established function as a product of glycolysis. Most of the mechanisms assembled in the review come from cell experiments and animal models, with some support from human observations, so the proposed lactate–lactylation axis is best understood as an emerging research framework rather than an established clinical mechanism or treatment target.

The metabolic sequence proposed for diabetic kidneys begins with hyperglycemia and hypoxia. These conditions can increase reactive oxygen species, inhibit the oxygen-dependent degradation of hypoxia-inducible factor-1α, and shift renal cells toward aerobic glycolysis. Stabilized HIF-1α induces genes including GLUT1, LDHA and HK2, while the metabolic regulator PKM2 can enter the nucleus and enhance HIF-1α-dependent transcription.

The resulting rise in glycolytic flux produces more lactate and may create a feed-forward loop: lactate-derived lysine lactylation at HIF-1α can interfere with its recognition by VHL, reducing ubiquitination and proteasomal degradation and sustaining glycolytic gene expression. The review presents this as a plausible amplification mechanism, but much of the direct evidence for it comes from non-diabetic kidney-injury models or other diseases. How lactate moves through kidney tissue may also determine which cells are exposed to it.

Renal monocarboxylate transporters have segment-specific roles, with MCT1 participating in basolateral lactate transport in proximal tubules, MCT2 and MCT7 appearing in thick ascending-limb and distal-convolution regions, and apical sodium-coupled transporters contributing to luminal reabsorption. Under glycolytic stress, MCT4 can export lactate and direct paracrine transfer toward other renal cells. Experimental work in ischemic kidneys links the MCT4 axis with endothelial inflammation and maladaptive repair, while evidence from lupus nephritis suggests that CD44 can increase injured-tubule lactate uptake.

These findings provide a transport framework, but the review notes that its functional architecture has largely been defined outside diabetic kidney disease and still requires direct validation in diabetic models. Enzymatic “writers” and “erasers” control lysine lactylation, the covalent addition of lactate-derived groups to lysine residues. Histone acetyltransferase p300 and its related CBP protein can use lactyl-CoA to write histone lactylation in several experimental systems, while HDAC1, HDAC2, HDAC3 and SIRT3 can remove selected lactylation marks.

Evidence from diabetic kidney models is strongest for alanyl-tRNA synthetases: AARS1 can promote H3K18 lactylation and STAT1 K193 lactylation in tubular cells. AARS2 has been linked to lactylation of the mitochondrial proteins PDHA1 and CPT2 in acute kidney injury models, a result that should not be treated as direct evidence from diabetic kidneys. SIRT3 has also been reported to remove H4K12 lactylation, restrain RUNX1 and α-SMA expression, and reduce fibrosis in diabetic models.

The review cautions that enzyme activity and substrate preferences vary by cell type and condition, so none of these proteins can yet be treated as a universal lactylation regulator throughout the diabetic kidney. Podocytes provide one example of how lactate could disturb the glomerular filtration barrier. In high-glucose podocyte models, increased MCT2 expression and reduced pyruvate dehydrogenase activity accompany lactate accumulation, reduced nephrin and ZO-1, higher histone lactylation, and increased collagen IV and α-SMA, a pattern associated with epithelial–mesenchymal transition.

Lactylation of leucyl-tRNA synthetase 1 at K970 has also been linked to sustained mTORC1 activation, impaired autophagic clearance of damaged mitochondria, increased reactive oxygen species and podocyte apoptosis; LARS1 knockdown improved renal outcomes in the cited experiments. Separately, podocyte-specific NLRP3 activation can produce sterile glomerular inflammation and impair autophagy. These findings show that lactate-associated injury is not necessarily a single linear pathway: lactylation-dependent effects operate alongside inflammasome signaling and other metabolic mechanisms.

In renal tubular epithelial cells, the proposed effects are closely tied to fibrosis, mitochondrial damage and ferroptosis. One study summarized in the review found that advanced glycation end products reduced CPT1A, CPT2 and PPARα while increasing glycolytic proteins HK2, PFKFB3 and LDHA. The accompanying rise in H3K14 lactylation at the KLF5 promoter was associated with lower E-cadherin and greater fibrotic signaling, while KLF5 knockdown shifted expression back toward epithelial markers.

Another axis involves ACSF2 K182 lactylation, which was linked to mitochondrial reactive oxygen species and tubular injury; targeted inhibition restored mitochondrial integrity in the experimental system. AARS1-dependent H3K18 and STAT1 K193 lactylation was also linked to ELOVL5 transcription, polyunsaturated fatty-acid synthesis, lipid peroxidation and ferroptosis. These results are mechanistically specific, but they remain primarily laboratory findings and do not establish that any one modification is a dominant driver in people with diabetic kidney disease.

Glomerular endothelial cells may provide a route through which metabolic signaling and inflammasome activation converge. Research summarized in the review indicates that hyperglycemia can increase IGFBP5 in endothelial cells, which activates PFKFB3 through an EGR1-dependent route and raises glycolytic activity. The resulting lactate accumulation was associated with increased H3K18 lactylation and NLRP3 inflammasome activation, while IGFBP5 knockdown reduced LDHA and PKM2, limited inflammasome activity, and attenuated endothelial-to-mesenchymal transition and fibrosis in experimental models.

Lactate can also influence inflammation without changing any protein modification: intracellular acidification can promote mitochondrial reactive oxygen species and PKR phosphorylation, which support NLRP3 assembly, and lactate itself can cleave pro-IL-1β and pro-IL-18 at the caspase-1 cleavage site in a non-enzymatic process. The review emphasizes that direct lactylation-specific evidence in diabetic glomerular endothelium remains scarce. Potential interventions intersect with the pathway at several levels, but clinical translation is early.

SGLT2 inhibitors already have established kidney-protective roles in diabetes, and preclinical observations suggest that some of their effects may involve correction of HIF signaling, reduced glucose uptake, lower lactate production or diminished lactylation. One cited study reported attenuation of podocyte injury and proteinuria by dapagliflozin in association with lower lactate generation and H4K12 lactylation, while another found that SGLT2 inhibition in diabetic mice increased anti-inflammatory macrophages and reduced harmful tubular–immune crosstalk. These findings do not establish lactylation as the principal clinical mechanism.

Herbal compounds that suppress lactate production or histone lactylation have likewise been studied mainly in cancer and inflammatory disease models, with very limited evidence generated specifically in diabetic kidney disease. The path to a useful biomarker is similarly constrained by the type of evidence currently available. Lactate could represent a systemic marker of metabolic and inflammatory burden, while lactylation enzymes or individual modification sites might indicate tissue-level injury, but this hierarchy remains a proposed framework.

Candidate markers require independent cohort validation, adjustment for age, sex, body mass index, renal function and comorbid illness, and standardized collection and laboratory methods. Their diagnostic and prognostic performance would need comparison with urinary albumin-to-creatinine ratio and estimated glomerular filtration rate, the established clinical measures discussed in the review. More fundamentally, diabetic kidney disease is multifactorial: lipotoxicity, pyroptosis, mitochondrial dysfunction, advanced glycation, immune-cell activation and other pathways can injure the kidney without lactate acting as the initiating cause.

The review therefore positions lactate as a potentially important cross-talk node and a valuable research direction, while not claiming that it is a universal driver or that targeting it alone would arrest disease progression.

Subject of Research: Mechanistic links among lactate signaling, lysine lactylation and diabetic kidney disease

Article Title: Mechanistic insights into lactate-driven pathogenesis in diabetic kidney disease

Article References: He, S., Yang, L., & Yin, R. (2026). Mechanistic insights into lactate-driven pathogenesis in diabetic kidney disease. Frontiers in Pharmacology, 17, Article 1950569. https://doi.org/10.3389/fphar.2026.1950569

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1950569

Keywords: diabetic kidney disease, lactate, lysine lactylation, metabolic reprogramming, HIF-1α, renal fibrosis, podocytes, renal tubules, SGLT2 inhibitors, NLRP3 inflammasome, Mechanistic, insights