Single-cell RNA sequencing and Mendelian randomization identify context-dependent LIPA-associated classical monocyte states in sepsis and breast cancer.

[BACKGROUND] Breast cancer remains one of the leading causes of cancer-related death in women, and sepsis is a major complication in cancer patients that worsens prognosis. Classical monocytes and the lysosomal acid lipase gene LIPA have been implicated in immune regulation, but their roles across these two disease contexts remain incompletely understood. Here, we used single-cell RNA sequencing and Mendelian randomization to investigate context-dependent LIPA-associated classical monocyte states in sepsis and breast cancer.

[METHODS] We analyzed single-cell RNA sequencing datasets from breast cancer and sepsis and integrated these analyses with Mendelian randomization. Differential expression analyses were performed to identify candidate genes associated with classical monocyte states, with particular focus on LIPA. An independent single-cell RNA sequencing dataset of peripheral blood mononuclear cells (PBMCs) from patients with breast cancer was further analyzed as supportive validation. Sensitivity analyses were performed to assess the robustness of the LIPA-based classification.

[RESULTS] Our analyses identified LIPA-associated classical monocyte states in sepsis and breast cancer, with distinct features across disease contexts. In breast cancer, higher LIPA expression in classical monocytes was associated with features consistent with an immunoregulatory state. Independent PBMC analysis identified circulating LIPA+ classical monocytes with a broadly comparable partition pattern, suggesting that this signal may extend beyond the tumor microenvironment. Mendelian randomization provided genetic support consistent with a potential association between LIPA and breast cancer risk. Sensitivity analyses confirmed that the main observations were not dependent on a single threshold definition.

[CONCLUSION] Single-cell RNA sequencing and Mendelian randomization analyses support context-dependent associations between LIPA and classical monocyte states in sepsis and breast cancer. Independent PBMC analysis provides supportive evidence that the LIPA-associated signal may also be detectable in circulation. These findings should be interpreted as hypothesis-generating and provide a rationale for future paired-sample, mechanistic, and experimental studies to clarify the functional relevance of LIPA in immune regulation and breast cancer.