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<p>Colorectal cancer (CRC) remains a significant global health challenge, characterized by high post-surgical recurrence and poor survival outcomes. This study explores the therapeutic potential of odoroside A (OA), a natural compound derived from <i>Nerium oleander</i>, focusing on its ability to modulate lipid metabolism and induce cancer cell death on CRC. In a subcutaneous xenograft tumor model with HT29 and RKO cells, OA achieved inhibition ratios of 81.07% and 78.26% at a dose of 1.5 mg/kg, respectively. Mechanistic insights revealed that OA induced lipid accumulation and triggered cell death through lipid peroxidation, primarily by inhibiting fatty acid oxidation (FAO) pathways. This effect was supported by decreased mitochondrial FAO activity and reduced expression of FAO-related proteins, including CPT1A, CPT1B, CPT1C, CPT2, and ACSL1. Additionally, OA targeted ubiquitin-specific peptidase 8 (USP8), promoting the ubiquitination and degradation of liver X receptor beta (LXRβ), a critical regulator of lipid metabolism. This downregulation of LXRβ further disrupted FAO. This study establishes a foundation for developing OA as a natural compound-based anticancer therapy for CRC and identifies a novel link between USP8 and LXRβ, offering new insights into lipid metabolism on CRC.</p><p></p>

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Targeting USP8 with odoroside A regulates LXRβ-mediated fatty acid metabolic reprogramming against colorectal cancer

  • 期刊论文

  • 发表日期：

    2026年7月8日

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  • Yan-yan Chen,
  • Fang-fang Liu,
  • Shi-yuan Wen,
  • Xiao-han Song,
  • Zi-han Ye,
  • Chun-cao Xu,
  • Yan-bei Tu,
  • He Huang,
  • Jin-jian Lu

摘要

Colorectal cancer (CRC) remains a significant global health challenge, characterized by high post-surgical recurrence and poor survival outcomes. This study explores the therapeutic potential of odoroside A (OA), a natural compound derived from Nerium oleander, focusing on its ability to modulate lipid metabolism and induce cancer cell death on CRC. In a subcutaneous xenograft tumor model with HT29 and RKO cells, OA achieved inhibition ratios of 81.07% and 78.26% at a dose of 1.5 mg/kg, respectively. Mechanistic insights revealed that OA induced lipid accumulation and triggered cell death through lipid peroxidation, primarily by inhibiting fatty acid oxidation (FAO) pathways. This effect was supported by decreased mitochondrial FAO activity and reduced expression of FAO-related proteins, including CPT1A, CPT1B, CPT1C, CPT2, and ACSL1. Additionally, OA targeted ubiquitin-specific peptidase 8 (USP8), promoting the ubiquitination and degradation of liver X receptor beta (LXRβ), a critical regulator of lipid metabolism. This downregulation of LXRβ further disrupted FAO. This study establishes a foundation for developing OA as a natural compound-based anticancer therapy for CRC and identifies a novel link between USP8 and LXRβ, offering new insights into lipid metabolism on CRC.