Background: Uncoupling of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) axis and impaired cGMP synthesis are hallmarks of chronic kidney disease (CKD). While sGC has been a target of therapeutic interest for CKD, clinical progress has been limited. Methods: In this single center, phase 1 study (NCT07021157), the pharmacokinetics (PK), pharmacodynamics (PD), and safety of SK-08, a novel, oral sGC activator, were evaluated. Healthy participants were randomized to SK-08 or placebo in the single-ascending-dose phase; in the food-effect phase, SK-08 10 mg was administered under fasted and fed conditions. cGMP was the key PD biomarker, and exposure-response analyses were performed. Results: Between 18th March 2025–17th June 2025, 16 participants were randomized and received SK-08 5 mg ( n = 3), 7.5 mg ( n = 3), or 10 mg ( n = 6), or placebo ( n = 4). Adverse events (AEs) were mild/moderate and resolved spontaneously, those with an incidence > 10% were hypotension (4/12, 33.3%) and dizziness (2/12, 16.7%). A higher C _max was associated with an increased incidence of adverse drug reactions (ADRs) across all SK-08 doses. Under fasted conditions, the absorption and time to peak plasma concentration of SK-08 was fairly rapid (median T _max 2.5–5.0 h). Administration after a high-fat meal prolonged the median T _max by 0.7 h; C _max and AUC were decreased by ~ 10%. Mean cGMP maximum percentage change (E _max ) increased dose dependently, from 5.99% at 5 mg to 27.19% at 10 mg, with a median time to E _{max of} 2.75–6.00 h. Conclusions: SK-08 was well tolerated in healthy participants and induced dose-related sGC activation. A potential association between C _max levels and the incidence of ADRs, and no clinically meaningful impact of food, was observed. These findings guide the optimization of a controlled-release formulation to maximize the therapeutic potential of SK-08. Trial registration: Chinadrugtrials.org.cn (CTR20250337). Registered 20,250,126 Clinicaltrials.gov (NCT07021157). Registered 20,250,512.