Angiotensin II–induced CHK1 phosphorylation at serine‐280: implications for JAK1–STAT3 activation and cardiac remodelling

We read with considerable interest the recent study by Xu and colleagues in the British Journal of Pharmacology, which reports that phosphorylation of checkpoint kinase 1 (CHK1) at serine-280 links angiotensin II (Ang II) to Janus kinase 1 (JAK1)–signal transducer and activator of transcription 3 (STAT3) activation and maladaptive cardiac remodelling in murine cardiomyocytes (Xu et al., 2025). The authors also show that inhibition of CHK1 with CCT245737 or that of JAK1 with upadacitinib limited hypertrophy, fibrosis and functional decline, even without lowering blood pressure. For the pharmacology community, this is a particularly notable finding because it places Ang II signalling in the heart, firmly beyond its haemodynamic effects. Our intention here is not to restate their conclusions, but rather to consider how these results could be validated and translated further. The suggestion that CHK1 directly phosphorylates JAK1 is unexpected and thought-provoking. CHK1 has long been viewed as a DNA damage checkpoint kinase, crucial for genome stability (Adam et al., 2018). Finding it redeployed in non-proliferative cardiomyocytes as a regulator of cytokine signalling speaks to the plasticity of stress kinases. Ang II is already known to activate AT₁ receptor-coupled cascades such as PI3K–Akt and p90RSK; it seems quite plausible that these intermediates converge on CHK1-S280 and thereby open the gate to JAK1–STAT3 (a schematic of this pathway is shown in Figure 1). What follows downstream is equally important. STAT3 can be cardioprotective in short bursts, for instance in ischaemic preconditioning, but when sustained it becomes a driver of fibrosis (Hilfiker-Kleiner et al., 2005). The fact that Ang II maintained CHK1–JAK1–STAT3 activity over several weeks suggests that chronic rather than acute STAT3 signalling underlies the remodelling phenotype. Xu et al. provide convincing functional evidence, yet additional biochemical and genetic approaches, such as kinase assays, phospho-site mapping or knock-in models, could, in our view, strengthen the case that CHK1 is a direct upstream kinase for JAK1. The pharmacological implications deserve attention. CHK1 inhibition with CCT245737 clearly improved outcomes in the study and earlier work has already described this compound as selective and orally active (McDonagh et al., 2021; Walton et al., 2015). But blocking CHK1 systemically raises predictable concerns about DNA repair in proliferating tissues. This suggests that CHK1 inhibition may be better suited for short-term use for example, in acute hypertensive stress rather than as a chronic strategy. One could imagine that targeted delivery, whether by nanoparticles or tissue-specific carriers, might make this option safer, though this remains speculative (Walton et al., 2015). JAK1 inhibition, by contrast, is already clinically established. Upadacitinib has a known safety and pharmacokinetic record in immune disease (Walton et al., 2015), making repurposing a more immediate possibility, although infection and haematological risks will need careful management. It might be worth considering lower doses or cardiovascular-specific formulations as second-generation approaches. In our view, the most useful way to frame this is to see haemodynamic and intracellular stress as complementary burdens: conventional therapies unload the first, while pathway blockade could relieve the second. Together, they may offer more than either alone. Clinically, the CHK1–JAK1 axis may also provide biomarkers. Phosphorylation of CHK1-S280 or JAK1–STAT3 activation could potentially be tracked not only in myocardial tissue but also in circulating vesicles. If validated, such measures might allow clinicians to identify patients most likely to respond and to follow treatment over time. The independence from blood pressure makes the pathway relevant well beyond classical hypertension. We can easily envisage roles in metabolic cardiomyopathy, chemotherapy-induced injury or age-related fibrosis settings, where residual risk remains despite apparently optimal haemodynamic therapy. Testing the pathway in these models may help determine whether it represents a general driver of maladaptive remodelling. In summary, Xu et al (2025) have uncovered an Ang II–CHK1-S280–JAK1 axis that reframes how we think about Ang II signalling in the heart. Rat