{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:04:58Z","timestamp":1790831098790,"version":"4.1.0"},"reference-count":110,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004374","name":"Chongqing Medical University","doi-asserted-by":"publisher","award":["BYKY-DS2024003"],"award-info":[{"award-number":["BYKY-DS2024003"]}],"id":[{"id":"10.13039\/501100004374","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004374","name":"Chongqing Medical University","doi-asserted-by":"publisher","award":["BYKY-CX2023004"],"award-info":[{"award-number":["BYKY-CX2023004"]}],"id":[{"id":"10.13039\/501100004374","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004374","name":"Chongqing Medical University","doi-asserted-by":"publisher","award":["XKYSJH-02"],"award-info":[{"award-number":["XKYSJH-02"]}],"id":[{"id":"10.13039\/501100004374","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004374","name":"Chongqing Medical University","doi-asserted-by":"publisher","award":["BYKY2024003"],"award-info":[{"award-number":["BYKY2024003"]}],"id":[{"id":"10.13039\/501100004374","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Heart failure (HF) and chronic kidney disease (CKD) frequently coexist and amplify one another through hemodynamic, neurohormonal, inflammatory, oxidative, and microvascular mechanisms. Impaired nitric oxide (NO)\u2013soluble guanylate cyclase (sGC)\u2013cyclic guanosine monophosphate (cGMP)\u2013protein kinase G (PKG) signaling represents a biologically plausible component of this cardiorenal interaction. However, clinical translation of sGC modulation requires careful interpretation because sGC stimulators and activators preferentially engage distinct biochemical states of the enzyme, and available evidence remains heterogeneous across compounds, phenotypes, and endpoint domains. This narrative review integrates mechanistic, preclinical, and clinical evidence for clinically evaluated sGC modulators, including vericiguat, riociguat, praliciguat, runcaciguat, avenciguat, and cinaciguat, with emphasis on HF\u2013CKD translational relevance. Vericiguat demonstrated benefit in a specific population of clinically stabilized patients with symptomatic chronic HF, LVEF below 45%, and a recent worsening-HF event. In VICTORIA, the reduction in the composite endpoint of cardiovascular death or first HF hospitalization was primarily driven by fewer HF hospitalizations, with no statistically significant reduction in cardiovascular death alone. Conversely, the VICTOR trial was neutral for its primary endpoint in stable ambulatory HFrEF, and HFpEF studies of vericiguat or praliciguat did not improve their prespecified biomarker, health-status, or exercise endpoints. In CKD populations, runcaciguat and avenciguat have shown short-term albuminuria reductions, but these surrogate signals have not established durable kidney protection, including long-term preservation of eGFR or prevention of kidney failure. To contextualize heterogeneous evidence, we propose an evidence-interpretation framework incorporating HF phenotype and clinical state, CKD phenotype, putative sGC redox biology, and endpoint domain. This framework is intended for evidence interpretation and hypothesis generation rather than patient-level treatment selection; no validated clinical assay defines tissue sGC redox state, and no prospective treatment-by-biomarker interaction has established redox-guided selection. Future studies should prioritize phenotype-enriched HF\u2013CKD populations, contemporary background therapy, and prespecified cardiovascular and kidney outcomes to define the clinical role of sGC modulation.<\/jats:p>","DOI":"10.3389\/fphar.2026.1954549","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:51:06Z","timestamp":1790830266000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Soluble guanylate cyclase modulation in heart failure and chronic kidney disease: mechanisms, clinical evidence, and translational boundaries"],"prefix":"10.3389","volume":"17","author":[{"given":"Wenhui","family":"Yuan","sequence":"first","affiliation":[{"name":"Department of Cardiology, Bishan Hospital of Chongqing Medical University, Bishan Hospital of Chongqing","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Bishan Hospital of Chongqing Medical University, Bishan Hospital of Chongqing","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changqing","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Bishan Hospital of Chongqing Medical University, Bishan Hospital of Chongqing","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"B1","unstructured":"A phase 2 randomized, double-blind, placebo-controlled study to assess the efficacy and safety of praliciguat in patients with biopsy-confirmed focal segmental glomerulosclerosis. 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