Pyruvate carboxylase (PC) replenishes tricarboxylic acid cycle intermediates, driving cancer metabolic reprogramming. To improve the metabolic stability of erianin, a potent PC inhibitor from Dendrobium chrysotoxum Lindl, we designed and synthesized 55 derivatives, culminating in the identification of CIB-Q22, which exhibited potent PC inhibition (IC50 = 1.74 nM) and suppressed HCC cell viability (IC50 = 25.18 nM), comparable to erianin. Notably, CIB-Q22 demonstrated significantly improved in vivo stability, with a half-life (T1/2 = 1.21 h) much longer than erianin (T1/2 ∼ 0.1 h). Mechanistically, CIB-Q22 suppressed HCC proliferation and metastasis by inducing apoptosis and ferroptosis. Moreover, it promoted mitochondrial oxidative stress and inhibited glycolysis, thereby sensitizing cells to glutamine deprivation. In vivo, CIB-Q22 exhibited comparable antitumor efficacy but improved safety compared to sorafenib. With its potent PC inhibition and favorable drug-like properties, CIB-Q22 represented a promising therapeutic candidate for HCC treatment.