SIRT5 (Sirtuin 5)

Our findings demonstrated that JPHYD effectively inhibited HCC growth and lung metastasis by dually modulating the SIRT5/Nrf2 signaling axis. This action simultaneously induced oxidative stress and disrupted mitochondrial metabolic reprogramming. JPHYD thus presents a promising multi-target therapeutic strategy for advanced HCC.

Notably, combining the SIRT5 inhibitor MC3482 with the cuproptosis inducer Elesclomol-Cu synergistically suppresses tumor growth in vivo, suggesting a promising therapeutic strategy. These findings elucidate mechanisms underlying cuproptosis resistance and propose a novel treatment approach for LUAD.

Notably, pharmacological MYC inhibition, which downregulates GCDH and elevates AKT1 glutarylation, synergizes with the AKT inhibitor afuresertib to suppress gastric cancer cell growth, revealing a potential therapeutic vulnerability. These findings link lysine metabolism to AKT-driven cancer progression and suggest therapeutic strategies targeting glutarylation dynamics.

In vivo, TAMM41 knockout markedly inhibits LUAD xenograft growth, accompanied by impaired mitochondrial respiration and increased apoptosis. Collectively, these findings identify TAMM41 as a mitochondrial oncogenic driver in LUAD and reveal a SIRT5-TAMM41-UBR5 axis that links lysine succinylation to mitochondrial metabolic control, highlighting TAMM41 as a potential therapeutic target.

We further summarize emerging therapeutic strategies, including small-molecule inhibitors targeting succinylation enzymes, metabolic interventions, and combination therapies designed to harness this pathway to overcome immunotherapy resistance. Finally, we discuss current challenges such as the incomplete mapping of enzyme-substrate relationships and the spatiotemporal heterogeneity of modifications within tumors, while highlighting future directions integrating CRISPR screening, AI prediction models, and single-cell multi-omics to advance precision targeting of succinylation for innovative cancer immunotherapies.

TEN exerts its anti-tumor effect in HCC cells by targeting SIRT5-succinylation. Therefore, TEN is a strong potential candidate anti-tumor drug for targeted HCC treatment.

Orthotopic co-transplantation of TNBC and EC cells with or without SIRT5 knockdown demonstrated that endothelial SIRT5 promotes increased tumor growth in vivo . These results suggest that targeting SIRT5 offers a potential therapeutic strategy to disrupt tumor angiogenesis and suppress TNBC progression by targeting the metabolic vulnerabilities of the tumor endothelium.

The primary SIRT isoform-selective residues for SIRT1 were Phe273, Phe297, Tyr280, and His363; for SIRT2, they were Phe119, His187, Val233, Phe235, and Leu239; for SIRT3, they were Leu248, Glu296, and Arg301; for SIRT5, they were Phe70, Tyr102, Gln140, and His158; and for SIRT6, they were Asp61, Trp69, His131, Trp186, Ser214, Arg218, and Leu239. In this study, we provided a deep cognizance of SIRT biology and a fruitful initiative for in vitro exploration of SIRT-selective inhibitors and an in silico contribution toward their clinical trial success.

A systematic description of the enzymatic and non-enzymatic regulatory mechanisms of succinylation, along with a summary of its functional roles and potential therapeutic value in different CNS diseases, especially the role of desuccinylases such as sirtuin 5 (SIRT5) as potential therapeutic targets, can provide a new theoretical basis and conceptual support for understanding the pathogenesis of CNS diseases and developing targeted intervention strategies. Future research should further clarify the core characteristics of disease-specific succinylation profiles and the integration patterns of multi-omics data, elucidate the molecular mechanisms of crosstalk among post-translational modifications, and promote the clinical translation of biomarkers and precision therapeutic drugs based on succinylation pathways.

In vivo xenograft experiments further validated that METTL17 knockdown markedly inhibited tumor growth and enhanced apoptosis. Collectively, these findings identify METTL17 as a critical regulator of mitochondrial function and energy metabolism in glioma and reveal a SIRT5-METTL17-RNF126 axis that governs METTL17 stability, providing new insights into glioma metabolic reprogramming and potential therapeutic targets.

Consistently, acetylation and deacetylation of GPRC5A at K348 by CREBBP and SIRT5 profoundly affect the cisplatin sensitivity as well as the ovarian tumorigenesis in mice bearing xenografts of SK-OV-3 ovarian cancer cells, respectively, and acetyl-K348-GPRC5A expression positively correlates with the poor prognosis of OC by analyzing the pathological sections and clinical data. Taken together, the present study identifies the GPRC5A acetylation at K348 and its stabilization as a hitherto uncharacterized mechanism controlling cisplatin resistance and OC recurrence, and may shed light on the early biomarker of OC recurrence and potential target for therapeutic intervention of chemoresistance of this malignancy.

Notably, the aggregation process shifts the magnetic resonance imaging (MRI) contrast from T1 to T2, enabling the real-time visualization of mitochondrial perturbations. This work establishes a versatile platform for designing neuropeptide-based nanoprobes with diagnostic and therapeutic potential for the treatment of breast cancer.