Integrated multi-omics profiling identifies aging-related molecular signatures and convergent interferon signaling in systemic lupus erythematosus.

128 nominally altered proteins annotated to aging-related biological processes were identified in SLE patients compared to healthy controls.

• The study combined in-house proteomic and phosphoproteomic data from 130 patients with SLE and 90 healthy controls (HCs)
• Aging-related biological processes represented included genomic instability, mitochondrial dysfunction, and epigenetic alterations
• Nominal P-value thresholds were used for exploratory feature selection, with FDR-adjusted P values used to assess robustness after multiple-testing correction
• Publicly available transcriptomic datasets comprising 1,461 SLE patients were also incorporated into the analysis

Phosphoproteomic analysis revealed 36 nominally altered phosphorylation sites in SLE, including previously unreported sites in IFI16 and PKCδ.

• Previously unreported phosphorylation sites identified in IFI16 were at positions S153 and S780
• Previously unreported phosphorylation sites identified in PKCδ were at positions S507 and S664
• These phosphorylation changes were analyzed across disease-status and disease-activity comparisons
• IFI16 and PKCδ are relevant to innate immune signaling and interferon responses

Clustering analysis demonstrated heterogeneous protein co-regulation patterns across disease states in SLE.

• Co-regulation patterns were not uniform across the SLE patient cohort
• The heterogeneity was identified across disease-status and disease-activity comparisons
• This finding suggests molecular subgroups may exist within the SLE patient population
• The clustering approach was applied to the 130 SLE patients and 90 healthy controls

Kinase activity inference suggested altered activity of TBK1 and IKKβ in SLE.

• Kinase-substrate enrichment analysis was used to explore potential regulatory programs
• TBK1 and IKKβ are kinases with established roles in innate immune signaling and NF-κB pathway activation
• Both kinases are relevant to interferon signaling pathways, which were identified as convergent across multi-omics layers
• Kinase activity was inferred rather than directly measured, representing a computational prediction

Transcription factor analysis highlighted STAT1, RELA, and PML as potential central regulatory nodes in SLE.

• Transcription factor annotation was used to explore potential regulatory programs
• STAT1 is a canonical mediator of interferon signaling
• RELA is a subunit of NF-κB, linking to IKKβ kinase activity findings
• PML (promyelocytic leukemia protein) was identified as a central node within the inferred regulatory network

Multi-omic alterations in SLE showed convergence toward shared signaling pathways, particularly interferon responses, rather than being randomly distributed.

• Convergence was observed across proteomic, phosphoproteomic, and transcriptomic data layers
• Transcriptomic datasets included 1,461 SLE patients from publicly available sources
• Cell-type-resolved transcriptomic comparison was used to explore the interferon signal across immune cell populations
• The convergence on interferon pathways was described as a key organizing principle linking aging-related molecular changes and SLE immune activation

The molecular alterations identified in SLE PBMCs overlap with aging-related biological processes including genomic instability, mitochondrial dysfunction, and epigenetic alterations.

• Proteins and phosphorylation sites were annotated using established aging-related gene resources
• The overlap was identified across 128 nominally altered proteins
• The study framed this as a 'hypothesis-generating framework for investigating the intersection between chronic immune activation and aging-related molecular remodeling in SLE'
• Analysis was conducted on peripheral blood mononuclear cells (PBMCs)