Hidalgo-Figueroa Maria, Delgado-Sequera Alejandra, Pérez-Ramos Anaid, Durán-Ruiz MªCarmen, Romero-Lopez-Alberca Cristina, Pérez-Revuelta Jose I, Marquez-Estefenn Ingrid, García-Mompó Clara, Moreno Jose Ma Villagrán, Berrocoso Esther
Neuropsychopharmacology and Psychobiology Research Group, University of Cadiz, Cádiz, Spain.
Biomedical Research and Innovation Institute of Cadiz (INiBICA), Cádiz, Spain.
Mol Med. 2025 Sep 26;31(1):294. doi: 10.1186/s10020-025-01343-x.
Lithium is a first-line treatment for bipolar disorder (BD), but only 30% of patients respond satisfactorily to monotherapy, and the biological basis for this variability remains unclear. This study aimed to identify potential biomarkers and therapeutic targets by analyzing olfactory neuroepithelium (ONE) cells from BD lithium non-responders (BDNR), responders (BDR), and control subjects.
Immunofluorescence and proteomic analyses of ONE cells were conducted. Blood samples were examined to improve accessibility for clinical applications.
Immunofluorescence and proteomic analyses of ONE cells revealed that BDNR cells exhibited impaired adhesion capacity, which was restored by lithium treatment in vitro. However, BDNR cells also showed significant alterations in cell morphology and cytoskeletal organization that were unaffected by lithium. Proteomic analysis identified significant changes in pathways associated with "cell morphology," with CDN2A highlighted as a key protein. In BDR cells, lithium treatment restored adhesion capacity but failed to reverse migration deficits. Proteomic analysis of BDR ONE cells identified differentially expressed proteins linked to neurotransmitter release, synaptic function, and mitochondrial activity, many of which were significantly modulated by lithium. Additionally, peripheral blood mononuclear cells from BDR patients displayed lower levels of RHOC protein, mirroring reductions seen in ONE BDR cells treated with lithium.
This study underscores cellular and proteomic differences between BDNR and BDR cells, with lithium exerting pronounced effects on BDR cells while having limited impact on BDNR cells. These findings advance our understanding of lithium responsiveness in BD and point to potential biomarkers and therapeutic targets for personalized treatment approaches.
锂盐是双相情感障碍（BD）的一线治疗药物，但只有30%的患者对单一疗法有满意反应，这种个体差异的生物学基础尚不清楚。本研究旨在通过分析BD锂盐无反应者（BDNR）、反应者（BDR）和对照受试者的嗅神经上皮（ONE）细胞来确定潜在的生物标志物和治疗靶点。
对ONE细胞进行免疫荧光和蛋白质组学分析。检测血样以提高临床应用的可及性。
对ONE细胞的免疫荧光和蛋白质组学分析显示，BDNR细胞表现出黏附能力受损，体外锂盐治疗可恢复该能力。然而，BDNR细胞还表现出细胞形态和细胞骨架组织的显著改变，这些改变不受锂盐影响。蛋白质组学分析确定了与“细胞形态”相关通路的显著变化，CDN2A被突出为关键蛋白。在BDR细胞中，锂盐治疗恢复了黏附能力，但未能逆转迁移缺陷。对BDR ONE细胞的蛋白质组学分析确定了与神经递质释放、突触功能和线粒体活性相关的差异表达蛋白，其中许多蛋白受到锂盐的显著调节。此外，BDR患者的外周血单核细胞中RHOC蛋白水平较低，这与用锂盐处理的ONE BDR细胞中的降低情况相似。
本研究强调了BDNR和BDR细胞之间的细胞和蛋白质组学差异，锂盐对BDR细胞有显著影响，而对BDNR细胞影响有限。这些发现加深了我们对BD中锂盐反应性的理解，并指出了个性化治疗方法的潜在生物标志物和治疗靶点。
