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<p>Sexual dimorphism plays a critical role in disease pathophysiology, but the subtlety and complexity of these differences, along with a lack of precise comparative methods, hinder the advancement of precision medicine and drug development. This limitation is particularly evident in metabolic dysfunction–associated steatotic liver disease (MASLD), where sex-specific molecular mechanisms remain insufficiently understood. To address this gap, we employed an advanced integrative N-glycoproteomics and proteomics approach to systematically analyze sex-biased molecular signatures in primary mouse hepatocytes (PMHs) under healthy and MASLD conditions. Our analysis identified 280 sex-biased proteins and 39 sex-biased N-glycosites, and KEGG enrichment revealed that female-biased molecules were primarily involved in lipid metabolism, while male-biased molecules were associated with inflammation and cytoskeletal remodeling. A combined dataset of 302 sex-biased molecules was further analyzed using protein–protein interaction (PPI) analysis and <i>Rc</i> value calculations, resulting in the identification of 21 hub proteins and 2 hub N-glycosites as MASLD-associated sex-biased signatures. Notably, MASLD amplified proteomic sex differences while attenuating them in N-glycosylation. Western blot validation of key signatures, including female-biased MVK and male-biased LGALS3, highlighted distinct molecular adaptations between the sexes in MASLD progression. Our study introduced an advanced analytical framework for high-resolution comparative molecular profiling by integrating N-glycoproteomics with proteomics, providing valuable insights into sex-biased molecular signatures, enhancing preclinical model development, and advancing sex-specific therapeutic strategies in MASLD research and broader biological systems.</p> Graphical Abstract <p></p>

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Advanced N-glycoproteomics and proteomics approach revealed sexually dimorphic molecular signatures in primary mouse hepatocyte

  • 期刊论文

  • 发表日期：

    2025年5月24日

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  • Qian Yang,
  • Yong Zhang,
  • He Zhang,
  • Zi Yang,
  • Yanruyu Feng,
  • Bengui Ye,
  • Puyang Gong,
  • Guangsheng Qian,
  • Dapeng Li

摘要

Sexual dimorphism plays a critical role in disease pathophysiology, but the subtlety and complexity of these differences, along with a lack of precise comparative methods, hinder the advancement of precision medicine and drug development. This limitation is particularly evident in metabolic dysfunction–associated steatotic liver disease (MASLD), where sex-specific molecular mechanisms remain insufficiently understood. To address this gap, we employed an advanced integrative N-glycoproteomics and proteomics approach to systematically analyze sex-biased molecular signatures in primary mouse hepatocytes (PMHs) under healthy and MASLD conditions. Our analysis identified 280 sex-biased proteins and 39 sex-biased N-glycosites, and KEGG enrichment revealed that female-biased molecules were primarily involved in lipid metabolism, while male-biased molecules were associated with inflammation and cytoskeletal remodeling. A combined dataset of 302 sex-biased molecules was further analyzed using protein–protein interaction (PPI) analysis and Rc value calculations, resulting in the identification of 21 hub proteins and 2 hub N-glycosites as MASLD-associated sex-biased signatures. Notably, MASLD amplified proteomic sex differences while attenuating them in N-glycosylation. Western blot validation of key signatures, including female-biased MVK and male-biased LGALS3, highlighted distinct molecular adaptations between the sexes in MASLD progression. Our study introduced an advanced analytical framework for high-resolution comparative molecular profiling by integrating N-glycoproteomics with proteomics, providing valuable insights into sex-biased molecular signatures, enhancing preclinical model development, and advancing sex-specific therapeutic strategies in MASLD research and broader biological systems.

Graphical Abstract