Background/Objectives: Hepatocellular carcinoma (HCC) remains difficult to treat because systemic therapy is constrained by limited selectivity, resistance, and toxicity. This study aimed to engineer selenium–chitosan nanoparticles loaded with sunitinib (SeNPs-Ch-SUN) to enhance hepatic delivery and improve anticancer activity against HCC. Methods: The developed system was characterized for particle size (PS), zeta potential (ZP), loading efficiency (LE%), in vitro release, and storage stability. Their cytotoxicity was evaluated in parental HepG2 and Huh-7 cells, multidrug-resistant HepG2 cells, SUN-resistant Huh-7 cells, and THLE-2 normal hepatocytes. In vivo hepatic distribution after intravenous administration was also assessed in rats. Results: SeNPs-Ch-SUN exhibited a mean PS of 93.62 ± 1.06 nm, positive ZP of +24.47 ± 1.31 mV, and LE of 83.8 ± 2.16%. FTIR supported drug association with the chitosan-stabilized selenium system. Compared with free sunitinib, SeNPs-Ch-SUN exhibited sustained drug release, with 51.17 ± 1.26% released at 24 h, whereas the free drug was almost completely released within 3 h. This controlled-release behavior translated in vivo into prolonged hepatic retention and superior liver exposure after intravenous administration. SeNPs-Ch-SUN significantly increased liver AUC_0–24 to 77.23 ± 10.56 µg/g·h, compared with 36.39 ± 9.66 µg/g·h for free SUN, corresponding to an approximately 2.1-fold increase in hepatic exposure. SeNPs-Ch-SUN enhanced cytotoxicity in parental and resistant HCC models, lowered IC₅₀ values, improved selectivity toward malignant cells, and reduced resistance index (RI) in MDR-HepG2 cells, while maintaining reduced toxicity toward normal hepatocytes relative to the free SUN. Conclusions: SeNPs-Ch-SUN represents a promising liver-directed nanoplatform for sunitinib delivery.

Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder characterized by ovarian dysfunction, hormonal imbalance, and emerging ferroptosis-related abnormalities. This study investigated the effects of alpha-lipoic acid (ALA), saxagliptin (Saxa), and their combination in a letrozole-induced PCOS model, with focus on the ovarian FGF21/NOX4–NRF2/HO-1 and ferroptosis-related pathways. PCOS was induced in female rats by oral letrozole administration for 21 days. Rats were allocated into control, PCOS, ALA, Saxa, and ALA/Saxa groups, followed by 14 days of treatment. Body weight, ovarian index, ovarian histopathology, reproductive hormones, oxidative stress markers, ovarian FGF21 and NOX4 expression, NRF2/HO-1 signaling, and ferroptosis-related markers, including Fe²⁺, GPX4, and SLC7A11, were assessed. Letrozole induced weight gain, ovarian hypertrophy, follicular disruption, endocrine imbalance, and ferroptosis-related alterations, marked by increased ROS, MDA, Fe²⁺, and NOX4, alongside reduced FGF21, NRF2/HO-1, GPX4, and SLC7A11. ALA or Saxa attenuated these alterations, whereas ALA/Saxa produced greater improvements in ovarian morphology, hormonal status, redox homeostasis, and ferroptosis-related markers. These effects were associated with FGF21 upregulation, NOX4 suppression, enhanced NRF2/HO-1 signaling, and preservation of GPX4 and SLC7A11. In conclusion, ALA/Saxa therapy markedly ameliorated letrozole-induced PCOS in rats, accompanied by restoration of ovarian FGF21/NOX4 homeostasis, associated with enhancement of NRF2/HO-1 antioxidant responses, and attenuation of ferroptosis-related alterations.