We study why diseased cells struggle to maintain protein homeostasis and how these vulnerabilities can be therapeutically exploited. Cancer cells, ageing tissues and vulnerable neurons all produce far more faulty proteins than healthy cells, so they lean heavily on the cellular machinery that keeps the proteome functional. Our goal is to therapeutically manipulate protein homeostasis in ways that selectively treat disease while preserving healthy tissue.
Protein homeostasis, or proteostasis, is the network of processes that governs how proteins are made, folded, trafficked and destroyed. A central focus of our lab is proteotoxic RNA splicing, a mechanism we first described (Science, 2024): disrupting the spliceosomal factor USP39 does not simply impair splicing but floods the cell with aberrant transcripts that are translated into aggregation-prone proteins. The resulting proteotoxic stress selectively compromises cells with high transcriptional and splicing activity. We combine molecular and cellular biology, genetically engineered disease models, CRISPR-based functional genomics, chemical biology and targeted protein degradation to translate these discoveries into therapies.
Our approach
Rather than targeting individual disease-causing proteins one at a time, we target the systems that keep the whole proteome intact. Because cancer, neurodegeneration and ageing all depend on the same proteostasis machinery for survival, a discovery in one disease often opens therapeutic doors in the others. This lets us treat protein homeostasis as a therapeutic platform, not a disease-specific pathway.
The clinical need is real. Aggressive cancers often lack druggable drivers or quickly escape existing drugs, and most neurodegenerative disorders still have no disease-modifying treatment. What these diseases share is chronic proteostatic stress. By identifying the mechanisms that allow diseased cells to tolerate that stress, we aim to convert these adaptive mechanisms into therapeutic vulnerabilities.
Research lines
1. Proteotoxic RNA splicing and proteostasis as therapeutic vulnerabilities in cancer
Building on our discovery of proteotoxic RNA splicing (Science, 2024), we investigate why aggressive tumours become critically dependent on spliceosome integrity and protein quality control, and how to turn that dependency against them. We define the molecular basis of proteotoxic RNA splicing, map the determinants of tumour sensitivity and resistance, and design strategies that deliberately overwhelm the proteostasis network to eliminate cancer cells. Beyond splicing, our work on IRGQ-mediated selective autophagy of MHC class I (Cell, 2024) uncovered a proteostasis-controlled route of tumour immune evasion, pointing to new ways to restore antigen presentation and boost anti-tumour immunity. Current efforts centre on new regulators of protein homeostasis, biomarkers of therapeutic response, first-in-class spliceosome-targeting degraders (Angewandte Chemie, 2026), and rational combinations with targeted protein degradation, autophagy, molecularly targeted therapies and immunotherapy.
2. Therapeutic modulation of proteostasis in neurodegeneration and ageing
Cancer is our primary focus, but much of the proteostasis machinery is shared with neurodegeneration and ageing. Proteotoxic RNA splicing was in fact first described in retinitis pigmentosa (Science, 2024), where destabilisation of the U4/U6.U5 tri-snRNP spliceosome generates aggregation-prone proteins that drive photoreceptor degeneration. We investigate how defective splicing fuels protein aggregation and neuronal loss, and we explore ways to restore proteostasis through splicing modulation, protein quality-control pathways and gene therapy. In parallel, we study the link between proteostasis, genome integrity and ageing: our recent work showed that faulty repair of DNA-protein crosslinks by the metalloprotease SPRTN activates cGAS-STING signalling, driving premature ageing and embryonic lethality (Science, 2026). From here, we aim to build proteostasis-based strategies that preserve tissue function and promote healthy ageing.
From discovery to therapy
An integrated translational platform bridges our fundamental biology and drug development. Combining CRISPR-based functional genomics, transcriptomics, proteomics, chemical biology and targeted protein degradation, we move discoveries from target identification and functional validation through to preclinical evaluation across several diseases. The platform has already delivered first-in-class USP39 degraders (Angewandte Chemie, 2026), a submitted European patent, and the translational venture SpliceTACs Bio.
Join us
We are a new group at the Instituto de Biomedicina de Sevilla (IBiS) building a team around these questions. We welcome curious, ambitious students and researchers who want to work at the interface of RNA biology, proteostasis and drug discovery, as well as clinical and industry partners interested in collaboration. If our work resonates with you, get in touch at cprieto-ibis@us.es
