PYCR1 (Pyrroline-5-Carboxylate Reductase 1)

Collectively, these findings suggest that PYCR1 may serve as a key target mediating DTX resistance in prostate cancer, and the emodin-DTX combination provides a promising potential clinical strategy to overcome such resistance. Finally, its functions and safety were also verified through in vitro experiments.

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.

ACADL functions as a mitochondria-associated tumor suppressor that impedes LUAD progression through activation of the FOXO3a/PUMA signaling pathway, underscoring its potential as a therapeutic target for LUAD.

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.

This validated mitochondrial risk model delivers a clinically actionable biomarker for BLCA prognosis stratification and guides personalized therapeutic selection, enabling precision treatment intensification.

This study provides a comprehensive analysis of glutamine metabolism in BLCA and introduces a clinically relevant prognostic model. PYCR1 was identified as a central metabolic regulator, underscoring its critical role in tumor development and progression.

Age-associated SL genes play critical roles in BRCA, with SLC7A5 highlighted as a promising biomarker and therapeutic target. These findings provide insights for early diagnosis and metabolism-based precision therapy.

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.

High-resolution structures revealed ligand-induced conformational changes in PYCR1, some involving significant rearrangements. Molecular dynamics simulations indicated that these conformations are accessible in the ligand-free enzyme, underscoring the intrinsic plasticity of PYCR1's active site.

This study revealed the heterogeneity of metabolic molecules in KIRP and established a prognostic machine learning model that enhances risk stratification and may optimize chemotherapy strategies in the management of KIRP.

This study demonstrates the contribution of stromal cell metabolism to MM progression. Inhibiting PYCR1 in BMSCs leads to less activin A release, limits oxidative phosphorylation in MM cells and enhances bortezomib efficacy.

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.