Cancer remains a leading cause of mortality worldwide, accounting for nearly 10 million deaths in 2020 [1], [2]. The World Health Organization (WHO) projects a 47% increase in cancer incidence by 2040 [3]. Platinum-based drugs, such as cisplatin and carboplatin, are cornerstone chemotherapeutic agents for a variety of cancers due to their broad-spectrum activity and unique mechanisms of action [4]. Cisplatin (CDDP) is the most widely used platinum drug, representing approximately 50% of the global platinum-based drug market. However, its clinical utility is limited by the rapid development of resistance and severe toxic side effects, including nephrotoxicity, ototoxicity, and gastrointestinal toxicity [5], [6], [7]. Carboplatin was developed to reduce the dose-limiting nephrotoxicity associated with cisplatin, offering predictable pharmacokinetics and lower emetogenic potential, which facilitate outpatient administration and improved tolerability. As a first-line treatment for ovarian cancer, germ cell tumors, and non-small cell lung cancer (NSCLC), carboplatin nonetheless shares mechanistic cross-resistance with cisplatin, mediated by reduced intracellular accumulation, enhanced DNA repair, and glutathione-mediated detoxification, and fails to overcome the core challenge of platinum resistance [8]. Both drugs also exhibit suboptimal efficacy against metastatic disease and dose-limiting toxicities—nephrotoxicity, ototoxicity, and neurotoxicity for cisplatin, and myelosuppression for carboplatin-which compromise patient safety, quality of life, and often necessitate dose reduction or treatment discontinuation [9], [10]. Therefore, the development of platinum-based prodrugs that retain potent antiproliferative activity while minimizing toxicity represents a promising direction for new chemotherapeutic agents.

The rapid systemic metabolism of platinum drugs, combined with the multifactorial pathogenesis of resistance and toxicity, motivates the exploration of natural product (NP)-based multi-target ligands conjugated within platinum prodrugs [11]. This strategy capitalizes on the ability of many NPs to simultaneously modulate multiple pathways involved in drug resistance and toxicity, while potentially improving tumor targeting. The design of NP‑platinum conjugates has gained considerable attention in recent years [12], [13], [14]. Moreover, the favorable safety profiles and structural diversity of NPs offer a viable path to prodrugs that improve the pharmacokinetics of platinum agents and address their limitations more comprehensively than single-target approaches [15], [16], [17], [18]. Preclinical studies have established the feasibility of platinum-NP conjugates for enhanced efficacy and reduced toxicity (Fig. 1) [19], [20], [21], [22], [23]. Despite these advancements, few studies have harnessed a natural product with inherent and potent organ-targeting capability to direct platinum drugs specifically to the tumor site, particularly for recalcitrant cancers like hepatocellular carcinoma (HCC), remains a paramount challenge.

18β-Glycyrrhetinic acid (GA), the primary active metabolite of glycyrrhizin, has a long history of use in traditional Chinese medicine, documented as early as the “Bencao Gangmu” for treating throat and cough conditions, peptic ulcers, and liver disorders [24]. Modern studies have revealed a range of pharmacological properties, including immunomodulatory, antioxidant, antipsoriatic, antitumor, neuroprotective, and hepatoprotective effects [25], [26], [27], [28]. Importantly, GA acts as a potent liver-targeting ligand via a dual-receptor mechanism: binding to GA receptors (GA-R) on hepatocytes and interacting with protein kinase Cα on hepatocellular carcinoma cells [29], [30]. This intrinsic liver specificity, combined with its ability to mitigate oxidative stress, modulate transporter proteins, and exert multi-target cytoprotective effects, makes GA an ideal candidate to address key limitations of platinum therapy-specifically, off-target toxicity and inadequate tumor accumulation.

Capitalizing on this synergy, we designed a novel GA‑platinum conjugate prodrug (Fig. 2). This strategy leverages: (i) the lipophilicity of GA to optimize the physicochemical properties of the platinum complex; (ii) its active liver-targeting capability to enhance tumor-selective drug delivery; and (iii) its intrinsic organ-protective mechanisms to reduce platinum-induced systemic toxicity. Guided by this prodrug concept, we designed and synthesized two GA-derived Pt(IV) precursors and evaluated their antitumor activities in vitro. Further investigations into the mechanism of action and in vivo efficacy of the lead Pt(IV) complex were also conducted.