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Objectives Histologic evaluation of renal tissue is pivotal in the diagnosis of lupus nephritis (LN) since flares contribute to poor outcomes. Nonetheless, molecular insights can add crucial information. We hypothesize that intrarenal gene expression is different in flares compared with control biopsies and conducted this study using a board transcriptome panel to test this hypothesis.Methods Whole renal tissue sections gene expression was evaluated in 21 formalin-fixed and paraffin-embedded (FFPE) LN samples from 9 patients using HTG Transcriptome panel. HTG EdgeSeq is based on quantitative nuclease protection assay (qNPA) and next-generation sequencing (NGS) technologies for targeted RNA without the need for nucleic acid extraction. Individual QC (quality control) for each sample using a strict QC threshold and subsequently an exploratory analysis with relaxed threshold were performed to identify differentially expressed genes (DEG).Results In the 8 biopsies that met the 2 sets of QC, comparing the gene expression between the 2 groups of the cohort, using a Benjamini - Hochberg adjusted p=0.05 and log2FoldChange cut-off = 1 several DEG directly and possibly indirectly related with LN pathogenesis pathways emerged. As top DEG upregulated in LN flare biopsies stood out tRNA Methyltransferase 61A (TRMT61A), Abhydrolase Domain-Containing Protein 11 (ABHD11), Neutrophil Cytosol Factor 4 (NCF4), Leukemia Inhibitory Factor (LIF), Mitogen-Activated Protein Kinase Kinase Kinase Kinase 1 (MAP4K1), Ras Association Domain Family Member 2 (RASSF2), Serpin Family A Member 3 (SERPINA3), Major Histocompatibility Complex, Class II, DR Beta 1 (HLA-DRB1), Baculoviral IAP Repeat Containing 7 (BIRC7), Beta-1,3-Glucuronyltransferase 2 (B3GAT2) and Cathepsin E (CTSE); as downregulated in LN flare biopsies, DEG such as Phosphoenolpyruvate Carboxykinase 1 (PCK1), Mitogen-Activated Protein Kinase Kinase Kinase 20 (MAP3K20),Conclusions A significant heterogeneity of transcripts were disclosed showing intricate pathways that differ depending on LN status. DEG such as HLA-DRB1, PCK1 and MAP4K1 had once more its role in LN pathogenesis confirmed; furthermore, transcripts profiling succeeded in identifying candidate markers for disease activity, new players in LN process pathways and new treatment targets such as TRMT61A, ABHD11, CTSE, NR4A3, BIRC7 and B3GAT2.