A CTCF-LDHB axis converts nuclear lactate availability into an H3K18 acylation switch that directs alternative splicing in hypoxic breast cancer

In hypoxic triple-negative breast cancer, nuclear lactate availability is set by a CTCF–LDHB axis and switches H3K18 lactylation versus acetylation to control TACC3 exon 3 splicing.

• Why it matters: Tumours with similar glycolytic rates can show different lactylation-linked chromatin and splicing outcomes, leaving how nuclear lactate and subtype context shape these epigenetic marks unclear.
• What they did: The study manipulated nuclear versus total lactate and CTCF/LDHB activity, then mapped how H3K18la or H3K18ac at a CTCF site downstream of TACC3 exon 3 recruits SMARCA4/hnRNPA1 or TRIM33/SRSF10 to direct splicing.
• The result: Low LDHB enables CTCF-dependent MCT1 to deliver lactate to the nucleus, promoting H3K18la and exon skipping that drives EMT, while LDHB inhibition restores exon skipping and suppresses tumour growth in vivo.

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