Liposomal honokiol attenuates dimethylhydrazine-induced colon carcinogenesis in rats through modulation of oxidative stress, inflammation, apoptosis, autophagy, and lipid metabolism pathways.

Abstract

<p>Colorectal cancer is one of the leading causes of cancer-related mortality worldwide, and its progression is strongly associated with oxidative stress, chronic inflammation, dysregulated apoptosis, and impaired autophagy. Although honokiol (HNK) possesses promising anticancer properties, its therapeutic application is limited by poor bioavailability and low aqueous solubility. Therefore, this study investigated the potential of liposomal honokiol nanoparticles (HNK-LNPs) as an advanced nanotherapeutic strategy to enhance the chemoprotective efficacy of HNK against dimethylhydrazine (DMH)-induced colon carcinogenesis in Wistar rats. Sixty rats were randomly allocated into six groups (n = 10): normal control, HNK, HNK-LNPs, DMH, DMH + HNK, and DMH + HNK-LNPs. Experimental treatments were continued for 10 weeks. DMH administration markedly increased serum tumor markers, including AFP, CEA, CA19-9, CA125, and CA15-3, as well as vascular endothelial growth factor (VEGF) levels. DMH exposure also induced severe oxidative stress, evidenced by elevated malondialdehyde (MDA) levels and depletion of total antioxidant capacity (TAC), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Moreover, DMH suppressed the NRF2/HO-1 antioxidant signaling pathway and significantly increased inflammatory mediators, including NF-κB, COX-2, TNF-α, IL-6, IL-1β, and nitric oxide (NO). In addition, DMH disrupted autophagic activity through downregulation of LC3-II and Beclin-1 and activated the PI3K/AKT/mTOR/SREBP-1c signaling pathway, leading to increased expression of fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1). DMH also inhibited apoptosis, as demonstrated by reduced expression of BAX, caspase-3, and TP53, along with increased BCL-2 expression. Histopathological and ultrastructural analyses confirmed marked colonic tissue injury and cellular abnormalities in DMH-treated rats. Co-administration of HNK partially ameliorated these alterations, whereas HNK-LNPs produced substantially greater protective effects. Treatment with HNK-LNPs restored antioxidant defenses, suppressed inflammatory and lipogenic signaling pathways, enhanced autophagy and apoptosis-related markers, and markedly improved histological architecture. Overall, HNK-LNPs demonstrated superior chemoprotective efficacy compared with free HNK, suggesting that liposomal delivery enhances the therapeutic potential of honokiol against DMH-induced colon carcinogenesis.</p>