Emerging natural product development strategies drive the therapeutic potential exploration and clinical translation of hydroxysafflor yellow A.

Hydroxysafflor yellow A (HSYA) is a structurally unique quinochalcone di-C-glycoside derived from safflower that exhibits broad-spectrum therapeutic activities, including cardiovascular protective, neuroprotective effects, anti-inflammatory, and antioxidant. As the principal active component in approved clinical injections, HSYA has demonstrated notable efficacy in acute ischemic stroke (IS). Recent breakthroughs in elucidating its biosynthetic pathway have enabled semi-synthetic and de novo production, laying the groundwork for industrial-scale application. However, HSYA's clinical translation remains hindered by physicochemical instability, poor oral bioavailability, short half-life, and fragmented mechanistic understanding. Additionally, inconsistent dosing regimens and the lack of in-depth mechanism exploration limit its therapeutic optimization. This review summarizes current advances in HSYA research, including its pharmacology, formulation strategies, and translational barriers. We propose integrative solutions involving nanostructure engineering, systems pharmacology, and artificial intelligence (AI)-assisted target identification to overcome current limitations. Together, these strategies aim to establish HSYA as a generalizable paradigm for advancing natural product-based therapeutics from bench to bedside.