Donisi Isabella, Balestrieri Anna, Del Vecchio Vitale, Bifulco Giovanna, Balestrieri Maria Luisa, Campanile Giuseppe, D'Onofrio Nunzia
Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via Luigi De Crecchio 7, 80138 Naples, Italy.
Food Safety Department, Istituto Zooprofilattico Sperimentale del Mezzogiorno, 80055 Portici, Italy.
Nutrients. 2025 Mar 13;17(6):1010. doi: 10.3390/nu17061010.
: Colorectal cancer (CRC) remains one of the most common and deadly malignancies worldwide, driven by metabolic reprogramming and mitochondrial dysfunction, which support tumor growth and progression. Several studies showed that nutrition is a contributing factor in the prevention and management of CRC. In this context, carnitines, amino acid derivatives abundant in food of animal origin, such as meat and milk, are crucial for mitochondrial function. Recently, l-carnitine and acetyl-l-carnitine have received particular attention due to their antioxidant, anti-inflammatory, and antitumor properties. However, to date, there is no conclusive evidence on the effects of l-carnitine and acetyl-l-carnitine in CRC or the underlying molecular mechanism. : In this study, we investigated in HCT 116 and HT-29 CRC cells the effects of l-carnitine and acetyl-l-carnitine on mitochondrial homeostasis by XF HS Seahorse Bioanalyzer and cell death pathways by flow cytometry and western blot assays. : Data showed that l-carnitine and acetyl-l-carnitine reduced cell viability ( < 0.001), modulated cellular bioenergetics, and induced oxidative stress ( < 0.001). These phenomena promoted autophagic flux and the mitophagy process via PINK1 and Parkin modulation after 72 h of treatment. Of note, the combined treatment with l-carnitine and acetyl-l-carnitine showed a synergistic effect and enhanced the effect of single carnitines on tumor cell growth and metabolic dysfunction ( < 0.05). Moreover, exposure to l-carnitine and acetyl-l-carnitine promoted CRC cell apoptosis, suggesting a mechanism involving mitophagy-related cell death. These data were associated with increased SIRT4 expression levels ( < 0.01) and the activation of AMPK signaling ( < 0.01). : Overall, the results, by supporting the importance of nutritional factors in CRC management, highlight l-carnitine and acetyl-l-carnitine as promising agents to target CRC metabolic vulnerabilities.
结直肠癌（CRC）仍然是全球最常见且致命的恶性肿瘤之一，由代谢重编程和线粒体功能障碍驱动，这些因素支持肿瘤的生长和进展。多项研究表明，营养是CRC预防和管理中的一个促成因素。在此背景下，肉碱是动物源性食物（如肉类和牛奶）中丰富的氨基酸衍生物，对线粒体功能至关重要。最近，左旋肉碱和乙酰左旋肉碱因其抗氧化、抗炎和抗肿瘤特性而受到特别关注。然而，迄今为止，关于左旋肉碱和乙酰左旋肉碱在CRC中的作用及其潜在分子机制尚无确凿证据。
在本研究中，我们通过XF HS海马生物能量分析仪研究了左旋肉碱和乙酰左旋肉碱对HCT 116和HT - 29 CRC细胞线粒体稳态的影响，并通过流式细胞术和蛋白质免疫印迹分析研究了其对细胞死亡途径的影响。
数据显示，左旋肉碱和乙酰左旋肉碱降低了细胞活力（<0.001），调节了细胞生物能量代谢，并诱导了氧化应激（<0.001）。这些现象在处理72小时后通过PINK1和Parkin调节促进了自噬通量和线粒体自噬过程。值得注意的是，左旋肉碱和乙酰左旋肉碱联合处理显示出协同效应，并增强了单一肉碱对肿瘤细胞生长和代谢功能障碍的影响（<0.05）。此外，暴露于左旋肉碱和乙酰左旋肉碱促进了CRC细胞凋亡，提示存在一种涉及线粒体自噬相关细胞死亡的机制。这些数据与SIRT4表达水平升高（<0.01）和AMPK信号通路激活（<0.01）相关。
总体而言，这些结果通过支持营养因素在CRC管理中的重要性，突出了左旋肉碱和乙酰左旋肉碱作为针对CRC代谢脆弱性的有前景药物。
