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Dual role of lactate in ferroptosis: Mechanisms, pathophysiology and therapeutic opportunities (Review)

  • Authors:
    • Qian Yu
    • Yu Kuang
    • Jie He
    • Li Yang
    • Xinjie Li
    • Hao Yu
  • View Affiliations / Copyright

    Affiliations: Laboratory Medical Department, Zigong Fourth People's Hospital, Zigong, Sichuan 643000, P.R. China, Laboratory Medical Department, Luzhou People's Hospital, Luzhou, Sichuan 646000, P.R. China, Department of General Surgery, Luzhou People's Hospital, Luzhou, Sichuan 646000, P.R. China, Department of Microbiology and Infectious Disease, School of Basic Medical Sciences, Peking University, Beijing 100191, P.R. China, Department of Clinical Laboratory, The First People's Hospital of Shuangliu District (West China Airport Hospital of Sichuan University), Chengdu, Sichuan 610000, P.R. China
    Copyright: © Yu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 41
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    Published online on: December 8, 2025
       https://doi.org/10.3892/ijmm.2025.5712
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Abstract

Ferroptosis, an iron‑catalyzed form of regulated cell death driven by lipid peroxidation‑induced membrane rupture, has emerged as a critical determinant of cellular fate across diverse physiological and pathological contexts. Simultaneously, lactate has undergone a notable conceptual transformation, evolving from being regarded as merely a glycolytic waste product to being recognized as a key signaling metabolite that modulates iron homeostasis, lipid dynamics, cellular redox balance and the immune response. This metabolic renaissance has revealed an intricate lactate‑ferroptosis regulatory network with implications for human disease. Notably, lactate exhibits diametrically contrasting effects on ferroptosis susceptibility: Promoting cell death in certain contexts while conferring protection in others. This apparent paradox, particularly evident when contrasting tumor and normal cell responses, suggests sophisticated context‑dependent regulatory mechanisms that are yet to be fully elucidated. The present review explores the molecular basis of both ferroptosis execution and lactate signaling, synthesizing recent advances that illuminate their dynamic interplay. Crucially, the present review discusses putative key contextual determinants, including the metabolic state, pH tolerance and antioxidant capacity, which may govern divergent roles of lactate in ferroptosis regulation. Furthermore, understanding these context‑specific mechanisms promises to unlock new therapeutic strategies for diseases ranging from cancer to neurodegeneration, where the lactate‑ferroptosis axis represents both a vulnerability and an opportunity.
View Figures

Figure 1

Molecular mechanism of ferroptosis.
(A) The canonical ferroptosis-regulating axis involves cystine
uptake via system Xc−, GSH biosynthesis and
GPX4-mediated reduction of PLOOH into their corresponding alcohols
(PLOH). NADPH provides electrons for recycling GSSG. (B) The
FSP1/CoQ10, DHODH/CoQ10 and GCH1/BH4/BH2 system serves as parallel
pathways to inhibit lipid peroxidation and ferroptosis. (C) The
peroxidation of phospholipids in the plasma membrane activates
PIEZO1, leading to the influx of Ca2+ and
Na+. This process, combined with the inactivation of the
Na+/K+ ATPase, results in the efflux of
K+. (D) The initiation and propagation of PLOOH form a
chain reaction with positive feedback. (E) PUFA and MUFA metabolic
pathways promote and inhibit lipid peroxidation, respectively. GSH,
glutathione; PLOOH, phospholipid hydroperoxides; PLOH, phospholipid
alcohol; GSSG, oxidized glutathione; FSP1, ferroptosis suppressor
protein 1; CoQ10, coenzyme Q10; DHODH, dihydroorotate
dehydrogenase; GCH1, GTP cyclohydrolase 1; BH4,
tetrahydrobiopterin; BH2, dihydrobiopterin; PIEZO1, piezo-type
mechanosensitive ion channel component 1; PUFA, polyunsaturated
fatty acid; MUFA, monounsaturated fatty acid; PL, phospholipid;
SFA, saturated fatty acid. Created with BioRender.com.

Figure 2

Lactate metabolism, lactylation and
the pathways involved in cells. Lactate is transported into cells
via MCTs and is generated through glycolysis or glutamine
decomposition in the cytoplasm. Once oxidized to pyruvate, pyruvate
can be metabolized through two major pathways: i) Entering
mitochondria for metabolism via the TCA cycle; or i) being
converted to glucose via gluconeogenesis. Intermediate products of
glycolysis and gluconeogenesis contribute to NADPH production
through the PPP. Malate can be converted to oxaloacetate via MDH,
generating NADPH, which supports fatty acid synthesis and GSSG
recycling. Citrate, another key metabolite, serves as a precursor
for lipid synthesis. Additionally, lactate can be converted into
lactyl-CoA, facilitating the lactylation of histone and non-histone
proteins, linking metabolism to epigenetic regulation. MCTs,
monocarboxylate transporters; TCA cycle, tricarboxylic acid cycle;
PPP, pentose phosphate pathway; MDH, malate dehydrogenase; GSSG,
oxidized glutathione; GLUTs, glucose transporters; LDH, lactate
dehydrogenase; HDACs, histone deacetylases; PDH, pyruvate
dehydrogenase; METTL3, methyltransferase like 3; HIFA,
hypoxia-inducible factor α; MDH, malate dehydrogenase; SLC38a1/2,
solute carrier family 38 member a 1/2. Created with BioRender.com.

Figure 3

Lactate-hepcidin axis regulates iron
homeostasis. Lactate enters cells via MCT1 and binds sAC,
triggering its conversion of ATP to cAMP. The cAMP activates PKA,
which enhances SMAD signaling. Activated SMAD upregulates HAMP
transcription, increasing hepcidin, the master regulator of iron
homeostasis. Hepcidin then binds FPN, causing its internalization
and degradation, which promotes cellular iron retention and lowers
circulating iron. MCT1, monocarboxylate transporter 1; sAC, soluble
adenylyl cyclase; cAMP, cyclic adenosine monophosphate; PKA,
protein kinase A; HAMP, human hepcidin gene; FPN, ferroportin 1.
Created with BioRender.com.

Figure 4

Lactate promotes lipid remodeling in
cells. Lactate is taken up via MCT1 and converted by LDH to
pyruvate and acetyl-CoA, which fuels de novo lipogenesis
through ACC, FASN, SCD1, FADS and ELOVL under the control of the
AMPK-SREBP1 axis. The resulting balance between MUFAs and PUFAs,
and their ACSL4-dependent incorporation into membranes, governs
lipid peroxidation and cellular susceptibility to ferroptotic cell
death. MCT1, monocarboxylate transporter 1; LDH, lactate
dehydrogenase; ACC, acetyl-CoA carboxylase; FASN, fatty acid
synthase; SCD1, stearyl-CoA desaturase 1; FADS, fatty acid
desaturases; ELOVL, elongation of very long-chain fatty acid; AMPK,
AMP-activated protein kinase; SREBP1, sterol regulatory
element-binding protein 1; MUFAs, monounsaturated fatty acids;
PUFAs, polyunsaturated fatty acids; ACSL4, acyl-CoA synthetase
long-chain family member 4. Created with BioRender.com.

Figure 5

Dual roles of lactate and lactylation
in ferroptosis regulation across cellular contexts. Lactate and
lactylation exhibit contrasting regulatory effects on ferroptosis
in normal vs. tumor cells through both lactylation-dependent and
-independent mechanisms. In lactylation-independent pathways,
lactate modulates cellular metabolism and redox homeostasis via
MCTs and GPR81 receptor signaling, with contrasting outcomes
observed between normal and malignant cell populations. In
lactylation-dependent pathways, lactate similarly demonstrates
contrasting effects in normal vs. tumor cell contexts through
post-translational protein modifications. PLOOH, phospholipid
hydroperoxides; ACSL4, acyl-CoA synthetase long-chain family member
4; METTL3, methyltransferase like 3; NOX4, NADPH oxidase 4; PPP,
pentose phosphate pathway; ROS, reactive oxygen species; SREBP1,
sterol regulatory element-binding protein 1; SCD1, stearoyl-CoA
desaturase 1; MUFAs, monounsaturated fatty acids; PUFAs,
polyunsaturated fatty acids; GPX4, glutathione peroxidase 4; FSP1,
ferroptosis suppressor protein 1; IDH1, isocitrate dehydrogenase 1;
GSH, glutathione; SGK1, serum- and glucocorticoid-inducible kinase
1; NEDD4L, neural precursor cell expressed developmental
downregulated protein; PCK2, phosphoenolpyruvate carboxykinase 2;
mtFAS, mitochondrial fatty acid synthesis; TFRC,
transferrin-transferrin receptor; MDA, malondialdehyde; NCOA4,
nuclear receptor coactivator 4; MDH2, malate dehydrogenase 2;
ZFP64, zinc finger protein 64; GCH1, GTP cyclohydrolase 1; FTH1,
ferritin heavy chain 1; NFS1, NFS1 cysteine desulfurase; GCLC,
glutamate-cysteine ligase catalytic subunit; LSD1, lysine-specific
demethylase 1; FosL1, Fos-like antigen 1; NSUN2, NOP2/Sun RNA
methyltransferase family member 2; IRI, ischemia-reperfusion
injury; HCC, hepatocellular carcinoma; ESCC, esophageal squamous
cell carcinoma; NSCLC, non-small cell lung cancer; MCT (1,4),
monocarboxylate transporter (1,4);
GPR81, G protein-coupled receptor 81. Created with BioRender.com.

Figure 6

Context-dependent mechanisms of
lactate in ferroptosis regulation. The context-dependent mechanisms
of lactate in ferroptosis regulation include: (A) Differential
metabolic enzyme expression profiles, (B) distinct cellular pH
homeostasis capacities and (C) varying antioxidant defense
capabilities. These mechanisms may underlie the distinct effects of
the context-dependent lactate-ferroptosis axis. IRI,
ischemia-reperfusion injury; MCT (1,4),
monocarboxylate transporter (1,4);
LDHA/B, lactate dehydrogenase A/B; CoQH2, ubiquinol; GSH,
glutathione; GPX4, glutathione peroxidase 4; SLC7A11,
cystine/glutamate antiporter solute carrier family 7 member 11;
FSP1, ferroptosis suppressor protein 1; NRF2, nuclear factor
erythroid 2-related factor 2. Created with BioRender.com.
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Copy and paste a formatted citation
Spandidos Publications style
Yu Q, Kuang Y, He J, Yang L, Li X and Yu H: Dual role of lactate in ferroptosis: Mechanisms, pathophysiology and therapeutic opportunities (Review). Int J Mol Med 57: 41, 2026.
APA
Yu, Q., Kuang, Y., He, J., Yang, L., Li, X., & Yu, H. (2026). Dual role of lactate in ferroptosis: Mechanisms, pathophysiology and therapeutic opportunities (Review). International Journal of Molecular Medicine, 57, 41. https://doi.org/10.3892/ijmm.2025.5712
MLA
Yu, Q., Kuang, Y., He, J., Yang, L., Li, X., Yu, H."Dual role of lactate in ferroptosis: Mechanisms, pathophysiology and therapeutic opportunities (Review)". International Journal of Molecular Medicine 57.2 (2026): 41.
Chicago
Yu, Q., Kuang, Y., He, J., Yang, L., Li, X., Yu, H."Dual role of lactate in ferroptosis: Mechanisms, pathophysiology and therapeutic opportunities (Review)". International Journal of Molecular Medicine 57, no. 2 (2026): 41. https://doi.org/10.3892/ijmm.2025.5712
Copy and paste a formatted citation
x
Spandidos Publications style
Yu Q, Kuang Y, He J, Yang L, Li X and Yu H: Dual role of lactate in ferroptosis: Mechanisms, pathophysiology and therapeutic opportunities (Review). Int J Mol Med 57: 41, 2026.
APA
Yu, Q., Kuang, Y., He, J., Yang, L., Li, X., & Yu, H. (2026). Dual role of lactate in ferroptosis: Mechanisms, pathophysiology and therapeutic opportunities (Review). International Journal of Molecular Medicine, 57, 41. https://doi.org/10.3892/ijmm.2025.5712
MLA
Yu, Q., Kuang, Y., He, J., Yang, L., Li, X., Yu, H."Dual role of lactate in ferroptosis: Mechanisms, pathophysiology and therapeutic opportunities (Review)". International Journal of Molecular Medicine 57.2 (2026): 41.
Chicago
Yu, Q., Kuang, Y., He, J., Yang, L., Li, X., Yu, H."Dual role of lactate in ferroptosis: Mechanisms, pathophysiology and therapeutic opportunities (Review)". International Journal of Molecular Medicine 57, no. 2 (2026): 41. https://doi.org/10.3892/ijmm.2025.5712
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