YAP and long non-coding RNAs in immune cells: context-dependent regulation and a hypothesis-generating synthesis of...

Yes-associated protein (YAP) is a transcriptional co-activator classically associated with tissue growth, mechanotransduction, and oncogenesis. Emerging evidence now identifies YAP as a critical regulator of immune cell function, influencing inflammatory signaling, antiviral responses, immune cell differentiation, and effector activity. In immune cells, YAP integrates biochemical and biomechanical cues to shape context-dependent outcomes, acting either as a promoter or suppressor of immune activation depending on cell type and microenvironment. Long non-coding RNAs (lncRNAs) have also emerged as key modulators of immune responses. Notably, in cancer and epithelial systems, multiple lncRNAs have been shown to influence YAP activity by controlling its stability, subcellular localization, and transcriptional output; whether analogous mechanisms operate in immune cells remains largely untested, with a single recent exception in macrophages. Here we synthesize this cross-system evidence to generate testable hypotheses about lncRNA-mediated regulation of YAP in immune contexts, rather than to report an established mechanism. In this review, we summarize current knowledge on YAP function across innate and adaptive immune populations and integrate it with emerging insights into lncRNA-mediated immune regulation, while identifying the evidence gaps. We highlight lncRNAs that directly regulate YAP signaling and additional candidates that converge on YAP-associated pathways, proposing a conceptual framework for how lncRNAs may fine-tune YAP-dependent immune responses. Understanding the lncRNA-mediated regulation of YAP in immune cells could provide new insights into immune modulation and identify prospective targets for therapeutic intervention in inflammatory, infectious, metabolic, and immune-related diseases.