Intermittent hypoxia (IH), the defining pathophysiological feature of obstructive sleep apnoea (OSA), has been shown to promote cardiac fibrosis by driving cardiac fibroblast (CF) activation. Single-cell RNA sequencing performed on heart tissue from mice exposed to IH revealed activation of Hedgehog signalling within CF populations and an increase in both expression and nuclear localization of the transcription factor GLI1 in CFs. These findings identify GLI1 as a candidate mediator linking IH exposure to CF phenotypic changes that underpin pathological fibrosis.
scRNA-seq of cardiac tissue from IH-exposed mice was used to characterize CF heterogeneity and signalling pathway changes associated with IH-induced fibrosis. The analysis highlighted upregulation of Hedgehog pathway components in CF clusters during IH exposure. The study specifically noted increased GLI1 expression and nuclear translocation in CFs under IH conditions, implicating GLI1 activation as a key cellular response to intermittent hypoxic stress.
To test causality, the investigators generated mice with myofibroblast-specific GLI1 overexpression as well as mice with GLI1 knockout in myofibroblasts. Overexpression of GLI1 in myofibroblasts recapitulated the effects of IH exposure, leading to CF activation and spontaneous cardiac fibrosis in the absence of IH. Conversely, genetic deletion of GLI1 attenuated CF activation in response to IH and reduced associated cardiac dysfunction. In parallel, pharmacological inhibition of GLI1 produced results consistent with the genetic deletion, reducing IH-induced CF activation and ameliorating functional cardiac impairment in experimental models. These complementary genetic and pharmacologic approaches support a central, causal role for GLI1 in IH-driven cardiac fibrosis.
Integrated RNA sequencing and chromatin immunoprecipitation sequencing (ChIP-seq) were employed to identify downstream effectors of GLI1. The combined genomic analyses indicated that enhanced glycolysis is a downstream effector of GLI1- and IH-induced fibrosis. Importantly, the glycolytic enzyme PKM2 was identified as a direct transcriptional target of GLI1 by ChIP-seq integration, linking GLI1 activation to metabolic reprogramming in CFs. The study thus proposes a mechanism in which IH induces GLI1 activation in CFs, GLI1 increases transcription of PKM2, and PKM2-driven glycolytic flux contributes to CF activation and fibrogenesis.
Both genetic deletion and pharmacological inhibition of GLI1 attenuated CF activation and improved cardiac function in IH-exposed models. The abstract reports that pharmacologic GLI1 inhibition reduced IH-induced CF activation and cardiac dysfunction, suggesting that targeting GLI1 can interrupt the pathological cascade from intermittent hypoxia to metabolic rewiring and fibrotic remodeling. Specific details regarding the pharmacologic inhibitor(s), dosages, administration schedule, or off-target effects are not provided in the abstract and therefore were not reported here.
To examine clinical relevance, the investigators assessed a cohort of patients with OSA. In 1,509 patients, elevated plasma lactate concentration—a surrogate marker of increased glycolytic activity—was positively associated with a higher cumulative incidence of heart failure events. This clinical observation aligns with the experimental mechanism linking IH, GLI1-driven PKM2 expression, increased glycolysis, and fibrotic cardiac remodeling. The abstract does not report detailed patient-level characteristics, adjustment covariates, lactate thresholds, or effect sizes; those details were not provided in the source abstract.
The study identifies GLI1 as a critical pro-fibrotic transcription factor mediating IH-induced CF activation and cardiac fibrosis through transcriptional upregulation of PKM2 and a shift toward enhanced glycolysis. Genetic and pharmacologic inhibition of GLI1 reduced CF activation and cardiac dysfunction in experimental models, supporting GLI1 as a promising therapeutic target for cardiac fibrosis, particularly in the context of OSA-related intermittent hypoxia. While the abstract establishes mechanistic links and a clinical association between lactate and heart failure incidence, it does not provide full experimental parameters, inhibitor details, or comprehensive patient cohort data; these would be needed to gauge translational readiness and to design clinical interventions.
Overall, the findings suggest that interrupting the GLI1→PKM2→glycolysis axis could mitigate IH-driven fibroblast activation and subsequent cardiac fibrosis, warranting further preclinical and clinical investigation into GLI1-targeted therapies for patients with OSA and related cardiac risk.