Targeting the NO-sGC-cGMP Pathway in Cancer Therapy-Related Cardiac Dysfunction: The Emerging Role of Vericiguat

Cancer therapy-related cardiac dysfunction (CTRCD) remains a major limitation of modern oncology, potentially compromising cardiovascular prognosis, functional status, and continuation of effective anticancer therapy. Vericiguat, an oral soluble guanylate cyclase (sGC) stimulator, enhances nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) signalling and has emerged as a biologically plausible candidate for translational evaluation in CTRCD. Chronic doxorubicin exposure reduces cardiac sGC activity, and genetic or pharmacological modulation of this pathway modifies experimental anthracycline injury. A 2024 peer-reviewed study in human AC-16 cardiomyocyte cells and primary skeletal-muscle cells showed increased cGMP and attenuation of NLRP3/MyD88-associated inflammatory and cytotoxic signalling with vericiguat. Two independent full-length studies published in 2026 extended this signal, implicating inhibition of ferroptosis through restoration of SLC7A11/GPX4-related defence and suppression of glycolysis, histone lactylation, and RELB-dependent inflammatory signalling. These findings strengthen mechanistic plausibility but remain preclinical. In heart failure, SOCRATES-REDUCED supported dose selection, VICTORIA demonstrated a modest reduction in cardiovascular death or first heart-failure hospitalization after recent worsening HFrEF, whereas VICTOR had a neutral primary endpoint in more stable ambulatory HFrEF; pooled analyses nevertheless suggest an overall treatment signal across the HFrEF risk spectrum. No randomized outcome trial has demonstrated efficacy specifically in CTRCD. ELEVATE (NCT05806138), a small randomized phase II trial in breast-cancer-associated CTRCD, remains without reported efficacy results as of 9 September 2026. Vericiguat should therefore be considered a biologically coherent and clinically testable strategy rather than an established cardio-oncology therapy.