Lactate-Driven CREB1 Lactylation Fuels Cisplatin Resistance in Ovarian Cancer via Neutrophil Traps
A lactate-driven modification of CREB1 triggers HMGB1 release and neutrophil traps that shield ovarian tumors from cisplatin. A nanoparticle peptide reversed this in mice.
Summary
Cisplatin resistance is a major reason ovarian cancer relapses. This preclinical study found that lactate, a byproduct of tumor metabolism, chemically tags the transcription factor CREB1 at lysine 122 (K122 lactylation) in resistant ovarian cancer cells and patient tissue. The tag, added by p300 and removed by SIRT1, redirects CREB1 to new DNA sites and switches on HMGB1. Tumors secrete HMGB1 in exosomes, and it activates neutrophils through TLR4 to release neutrophil extracellular traps (NETs), which protect cancer cells from chemotherapy. A lipid nanoparticle carrying a lactylation-deficient CREB1 K122R competitor peptide slowed tumor growth with cisplatin in mouse xenografts and lowered serum exosomal HMGB1. The work is early-stage and rests on cell lines, small patient cohorts, and mice.
Detailed Summary
Ovarian cancer is the most lethal gynecologic malignancy. Most patients are diagnosed at advanced stages, and although about 75-80% respond initially to platinum chemotherapy, roughly 70% eventually relapse with resistant disease. Tumors are often rich in lactate, which can also act as a signaling molecule by attaching to proteins as lysine lactylation (Kla). Whether this modification helps drive cisplatin resistance in ovarian cancer was largely unknown.
The researchers compared cisplatin-resistant ovarian cancer cell lines (SKOV3/DDP and A2780/DDP, generated by gradual dose escalation) with their parental lines. Quantitative lactyl-proteomics identified CREB1 lysine 122 as a hyperlactylated site specific to resistant cells and to tissue from resistant patients. The authors report that p300 acts as the lactylation 'writer' and SIRT1 as the 'eraser'. Mutant versions of CREB1 mimicking lactylation (K122Q) or blocking it (K122R) were tested in cells and xenografts. CUT&Tag chromatin profiling, NET assays, and patient serum measurements were used to trace the downstream mechanism.
According to the abstract, the lactylation-mimicking K122Q mutant increased cell survival and tumor growth under cisplatin, whereas K122R sensitized cells. K122 lactylation reshaped CREB1's chromatin binding, shifting it from promoters toward distal enhancers and expanding its target genes. This activated a NETosis-related program, with HMGB1 as a key effector. Lactylated CREB1 boosted HMGB1 transcription, and HMGB1 was released in exosomes. It then engaged TLR4 on neutrophils to trigger NET formation, which the authors describe as a chemoprotective niche. In patients, cisplatin resistance was associated with higher tumor K122 lactylation and higher serum exosomal HMGB1; the methods also describe correlating exosomal HMGB1 with plasma MPO-DNA, a NET marker.
For therapy, the team built a tumor-targeted lipid nanoparticle delivering a K122R competitive peptide. Alone and especially with cisplatin, it suppressed tumor growth in mouse models and reduced serum exosomal HMGB1, which the authors interpret as reversal of chemoresistance. The study proposes a lactate-CREB1 K122la-HMGB1-NETs axis linking metabolism, epigenetics, and immunity, with potential biomarkers (exosomal HMGB1) and a nanomedicine strategy.
Caveats: the full text supplied ended partway through the Methods section, so this summary relies on the abstract for results and discussion, and exact effect sizes are not reported here. The evidence is preclinical, using two cell lines, nude-mouse xenografts, and small human cohorts (12 tissue samples, with an unbalanced 4 sensitive versus 8 resistant split, and 50 serum samples). Clinical benefit, safety of the nanoparticle, and generalizability remain untested.
Key Findings
- CREB1 K122 lactylation is enriched in cisplatin-resistant ovarian cancer cells and patient tumor tissue, regulated by p300 (writer) and SIRT1 (eraser).
- Lactylation-mimic CREB1 K122Q increased resistance and tumor growth; lactylation-deficient K122R sensitized cells to cisplatin.
- K122la shifts CREB1 binding from promoters to distal enhancers, activating NETosis programs and HMGB1 transcription.
- Exosomal HMGB1 engages neutrophil TLR4 to trigger NETs; resistant patients had higher serum exosomal HMGB1.
- A lipid nanoparticle delivering a K122R competitive peptide plus cisplatin suppressed xenograft growth and lowered serum exosomal HMGB1.
Methodology
Preclinical mechanistic study using parental versus cisplatin-resistant ovarian cancer cell lines (SKOV3, A2780), lactyl-proteomics, CRISPR CREB1 knockout, K122Q/K122R mutants, and CUT&Tag chromatin profiling. Human validation used 12 tumor tissue samples (4 sensitive, 8 resistant) and serum from 50 patients (25 per group). Efficacy of a tumor-targeted lipid nanoparticle peptide was tested in subcutaneous nude-mouse xenografts.
Study Limitations
Evidence comes from cell lines, immunodeficient nude mice, and small, unbalanced human cohorts, so the findings may not generalize. Full results were not available in the supplied text, so effect sizes, nanoparticle safety, off-target effects, and durability are unassessed. The causal role of NETs in vivo and the specificity of the competitive peptide need independent confirmation.
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