Sodium–glucose cotransporter (SGLT) inhibitors are increasingly recognized for effects beyond glycaemic control, including reported anticancer activity. Prior work with selective SGLT2 inhibitors implicated suppression of tumour cell proliferation and modulation of metabolic signalling pathways such as AMPK/mTOR and PI3K/AKT. The extent to which dual SGLT1/2 inhibition influences epigenetic regulators has been less explored. This study evaluated the dual SGLT1/2 inhibitor sotagliflozin for anticancer activity in breast (MCF-7) and lung (A549) cancer cell models and examined its association with epigenetic enzyme modulation.
In both MCF-7 and A549 cell lines, sotagliflozin treatment produced multiple antineoplastic effects reported by the authors. Sotagliflozin reduced cell viability and clonogenic survival, and impaired cellular behaviours essential for metastasis by decreasing migration and invasion. These phenotypic endpoints together indicate broad antiproliferative and anti-migratory activity in the two tested cancer cell models.
Cellular changes accompanying the phenotypic effects included induction of G2/M cell-cycle arrest. Sotagliflozin treatment increased activation of AMPK, a central metabolic regulator, and produced changes in PTEN-AKT-mTOR signalling. The reported pattern links metabolic sensing and growth-control pathways with the observed reductions in proliferation and survival, consistent with previously described mechanisms for SGLT2 inhibitors in cancer models.
To probe possible interactions with epigenetic enzymes, the investigators performed molecular docking analyses against DNA methyltransferases DNMT1, DNMT3A, and DNMT3B. Docking predicted favourable binding between sotagliflozin and these DNMTs, with the strongest predicted binding affinity to DNMT1 (reported binding energy −8.9 kcal/mol in the source). These computational results motivated experimental assessment of DNMT enzymatic activity and expression following drug exposure.
Consistent with docking predictions, sotagliflozin treatment was associated with reduced total DNMT enzymatic activity in the cell lines studied. The authors report decreased DNMT1 mRNA and protein abundance after treatment. These findings indicate that sotagliflozin exposure correlates with downregulation of a key maintenance DNA methyltransferase at both transcript and protein levels, and with reduced overall DNMT activity.
Beyond DNMTs, sotagliflozin treatment was associated with reduced protein abundance of multiple histone deacetylases from class I and class II families. Specifically, the study reports decreased levels of HDAC1–4 and HDAC6 in both MCF-7 and A549 cells. This coordinated reduction in DNMT1 and HDAC proteins suggests concurrent modulation of DNA methylation and histone deacetylation machinery following sotagliflozin exposure.
The authors also documented autophagy-associated changes after sotagliflozin treatment. Reported findings included increased acidic vesicular organelles—an indicator of autophagic or lysosomal activity—and elevated abundance of autophagy markers LC3-II and Beclin-1. These observations indicate that autophagy pathways are engaged alongside changes in metabolic signalling and epigenetic regulator abundance.
Collectively, the reported results demonstrate that sotagliflozin exerts broad anticancer effects in the tested breast and lung cancer cell lines, including reductions in viability, clonogenicity, migration, and invasion, accompanied by G2/M arrest and activation of AMPK with alterations in PTEN-AKT-mTOR signalling. Molecular docking and biochemical assays link sotagliflozin exposure to predicted and observed decreases in DNMT activity and DNMT1 expression, along with lowered protein levels of class I and II HDACs, and induction of autophagy markers.
The investigators characterize these findings as preliminary evidence that dual SGLT1/2 inhibition may modulate epigenetic regulators in cancer cells. The source explicitly notes that further studies are required to determine whether the epigenetic changes contribute directly to the observed cellular responses or are secondary consequences of metabolic perturbation. The abstract does not provide additional experimental details such as dose ranges, treatment durations, or quantitative effect sizes; those specifics were not reported in the source abstract and would need to be consulted in the full article for mechanistic and translational interpretation.
Overall, the study supports a multifactorial model whereby sotagliflozin impacts metabolic signalling, epigenetic enzyme abundance, and autophagy-related processes in MCF-7 and A549 cells, yielding anticancer effects that merit further mechanistic and in vivo investigation.