Shiguo Sun

Construction of SLC16A1/3 Targeted Gallic Acid-Iron-Embelin Nanoparticles for Regulating Glycolysis and Redox Pathways in Cervical Cancer

SLC16A1 and SLC16A3 (SLC16A1/3) are highly expressed in cervical cancers and associated with the malignant biological behavior of cancer. SLC16A1/3 is the critical hub for regulating the internal and external environment, glycolysis, and redox homeostasis in cervical cancer cells. Inhibiting SLC16A1/3 provides a new thought to eliminate cervical cancer effectively. There are few reports on effective treatment strategies to eliminate cervical cancer by simultaneously targeting SLC16A1/3. GEO database analysis and quantitative reverse transcription polymerase chain reaction experiment were used to confirm the high expression of SLC16A1/3. The potential inhibitor of SLC16A1/3 was screened from Siwu Decoction by using network pharmacology and molecular docking technology. The mRNA levels and protein levels of SLC16A1/3 in SiHa and HeLa cells treated by Embelin (EMB) were clarified, respectively. Furthermore, the Gallic acid-iron (GA-Fe) drug delivery system was used to improve its anti-cancer performance. Compared with normal cervical cells, SLC16A1/3 mRNA was over-expressed in SiHa and HeLa cells. Through the analysis of Siwu Decoction, a simultaneously targeted SLC16A1/3 inhibitor EMB was discovered. It was found for the first time that EMB promoted lactic acid accumulation and further induced redox dyshomeostasis and glycolysis disorder by simultaneously inhibiting SLC16A1/3. The gallic acid-iron-Embelin (GA-Fe@EMB) drug delivery system delivered EMB, which had a synergistic anti-cervical cancer effect. Under the irradiation of a near-infrared laser, the GA-Fe@EMB could elevate the temperature of the tumor area effectively. Subsequently, EMB was released and mediated the lactic acid accumulation and the GA-Fe nanoparticle synergistic Fenton reaction to promote ROS accumulation, thereby increasing the lethality of the nanoparticles on cervical cancer cells. GA-Fe@EMB can target cervical cancer marker SLC16A1/3 to regulate glycolysis and redox pathways, synergistically with photothermal therapy, which provides a new avenue for the synergistic treatment of malignant cervical cancer.

Repurposing HIV protease inhibitors as senotherapeutic agents in cervical cancer: Dual targeting of CDK1/6-cell cycle arrest and p53/p21/p16 signaling axis

The clinical management of cervical cancer remains constrained by limited therapeutic options and a paucity of targeted pharmacological interventions. Drug repurposing emerges as a promising strategy to expedite oncological therapeutics development. This study systematically investigates the antineoplastic potential of HIV protease inhibitors saquinavir (SQV) and tipranavir (TPV) through multimodal mechanistic validation. In vitro analyses demonstrated dose-dependent inhibition of cervical cancer cell proliferation accompanied by significant upregulation of senescence-associated β-galactosidase (SA-β-Gal) activity. Molecular characterization revealed concomitant activation of senescence-regulatory proteins p53, p21, and p16, suggesting induction of tumor-suppressive senescence pathways. Transcriptomic profiling of inhibitor-treated SiHa cells identified critical cell cycle regulators CDK1 and CDK6, findings corroborated by molecular docking simulations revealing high-affinity binding to cyclin-dependent kinases (-32.0607 to -47.6820 kJ/mol). In vivo validation using xenograft models demonstrated comparable tumor growth inhibition to doxorubicin with preserved host viability and negligible systemic toxicity. Mechanistic integration revealed dual pathway modulation: G1-phase cell cycle arrest mediated through CDK1/6 suppression and coordinated activation of the p53/p21/p16 senescence signaling axis. These findings establish SQV and TPV as multi-targeted senotherapeutic agents, providing preclinical rationale for repurposing HIV antivirals as novel therapeutic strategy against cervical malignancies.