PRO-C3 (Pyrroline-5-carboxylate reductase)

Co-crystal structures of PYCR1 with combinations of allosteric inhibitors, NADH, and L-P5C/proline analogs suggest the inhibitors can bind to the ternary PYCR1-L-P5C-NAD(P)H complex in addition to the free enzyme, consistent with a mixed mechanism of inhibition. The discovery of an allosteric inhibitor binding groove that accommodates multiple fragments heralds a new era of PYCR1 inhibitor design.

Collectively, our findings establish PYCR1 as a critical regulator of EGFR and TLR signaling pathways, driving lung cancer progression. Targeting PYCR1 with pharmacological inhibitors such as PYCR1-IN-1 offers a promising strategy for combating EGFR- and TLR-driven NSCLC progression.

P=N/A, N=45, Recruiting, Milton S. Hershey Medical Center | Trial primary completion date: Oct 2025 --> May 2026

Moreover, immune infiltration analysis revealed PYCR1-driven remodeling of the tumor immune microenvironment. Collectively, our findings establish PYCR1 as a mitochondrial regulator integrating metabolic and immunological mechanisms in OS and highlight its potential as a biomarker and therapeutic target for precision diagnosis and mitochondria-targeted interventions.

On the other hand, in fibrotic disorders, PYCR1-mediated proline metabolism has been linked to the progression of pulmonary, myocardial, and cutaneous fibroses. Notably, although PYCR1-targeted small-molecule inhibitors have demonstrated therapeutic potential in preclinical studies, their clinical translation is yet to be validated.

Our review suggests that exercise shows potential in modulating physiological and molecular pathways' among HNC survivors. Although only 3 studies were eligible for inclusion, these benefits might potentially translate into improvements in health-related outcomes amongst HNC survivors. Future large-scale trials with standardized exercise protocols and extended follow-up periods might improve our understanding of the long-term effects of exercise on biomarkers and survivorship outcomes in HNC.PROSPERO Registration Number: CRD42024508084.

In vivo experiments confirmed that the PYCR1/H3K18la/SLC6A14 axis is critical for hypoxia-driven BC growth and metastasis. In summary, Hypoxia-induced PYCR1 enhances glycolysis, leading to increased lactate production and elevated H3K18la levels, which upregulates SLC6A14 transcription and glutamine catabolism, thereby promoting BC growth and metastasis.

P=N/A, N=45, Recruiting, University of Nottingham

Our results suggest that the inhibitory effects of 9-DAA are due to nicotinamide adenine dinucleotide. We further demonstrated that PYCR1 was elevated under hypoxia and in 3D spheroids in colon cancer and that 9-DAA effectively inhibited cancer progression under cancer-mimicking conditions and in vivo.

SMYD2 was associated with PYCR1 expression. SMYD2 upregulated PYCR1 expression through H3K4me3, subsequently activating the PINK1/Parkin mitophagy pathway, which supports maintenance of BCSC stemness.

High PYCR1 expression is an independent risk factor for poor prognosis in BLCA patients and can serve as a significant indicator for clinical decision-making as well as a marker for predicting sensitivity to chemotherapeutic agents and the efficacy of immunotherapy.

This study highlights the critical role of PYCR1 in driving ESCC progression and metastasis, underscoring its potential as a promising therapeutic target for managing this malignancy.