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Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology...
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Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology—2nd Edition

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 25 May 2026 | Viewed by 9590

Special Issue Editors

Dr. Michele Aventaggiato

E-Mail Website
Guest Editor
Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161 Rome, Italy
Interests: sirtuins; metabolism; extracellular vesicles; autophagy; mitophagy; apoptosis
Special Issues, Collections and Topics in MDPI journals
Dr. Marco Tafani

E-Mail Website
Guest Editor
Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy
Interests: sirtuins; hypoxia inflammation; metabolism; autophagy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The sirtuin family of proteins is a class of enzymes that is highly conserved from yeast to humans, possessing a high homology in their sequences and cellular functions, underlying the fact that these proteins play important physiological roles. Seven mammalian sirtuins have been identified, which are characterized by different cellular functions, structures and localizations that can vary based on different stimuli. Sirtuins were first characterized as histone deacetylases, but the presence of non-histone targets underline their involvement in many cellular processes such as the cell cycle, differentiation, senescence, stress response, inflammation, aging, and metabolism. On the other hand, sirtuins are involved in several pathological conditions, such as neurodegenerative disorders, cardiovascular diseases, metabolism-related disorders, carcinogenesis, and tumor development, in which they can act as disease promoters or protective factors based on their targets and functions. Nuclear sirtuins, due to their epigenetic role, and mitochondrial sirtuins, due to their involvement in several metabolic processes, such as the tricarboxylic acid cycle, respiratory chain, fatty acid β-oxidation, ketogenesis, glutamine metabolism, etc., represent an important object of investigation hallmarks of carcinogenesis, represented by metabolic reprogramming and uncontrolled cell proliferation. In a broader analysis that also considers the influence of sirtuins in physiological and pathological conditions, this class of proteins represents a promising potential target of molecular and pharmacological strategies that could counteract the effects of several pathological conditions acting at various levels in molecular and cellular mechanisms. This Special Issue aims to collect and summarize the latest findings on the potential of sirtuin-based pharmacological interventions to modulate activity and counteract damage and the onset of pathological states, favoring the physiological homeostasis of tissues.

Dr. Michele Aventaggiato
Dr. Marco Tafani
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • sirtuins
  • metabolism
  • cancer
  • hypoxia
  • damage recovery
  • cell death

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Related Special Issue

Published Papers (6 papers)

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Research

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21 pages, 3232 KB  
Article
A Combined SIRT5 Activation and SIRT3 Inhibition Prevents Breast Cancer Spheroids Growth by Reducing HIF-1α and Mitophagy
by Federica Barreca, Michele Aventaggiato, Mario Cristina, Luigi Sansone, Manuel Belli, Maria Beatrice Lista, Gaia Francisci, Sergio Valente, Dante Rotili, Antonello Mai, Matteo Antonio Russo and Marco Tafani
Pharmaceuticals 2026, 19(1), 23; https://doi.org/10.3390/ph19010023 - 22 Dec 2025
Viewed by 1548
Abstract
Background/Objectives: Metabolic reprogramming is an essential feature of tumors. Mitochondrial sirtuins SIRT3 and SIRT5 differently regulate glutamine metabolism with SIRT5 inhibiting glutaminase (GLS) and SIRT3 increasing glutamate dehydrogenase (GDH). Considering the important and interconnected role of glutamine, SIRT3 and SIRT5 for cancer growth [...] Read more.
Background/Objectives: Metabolic reprogramming is an essential feature of tumors. Mitochondrial sirtuins SIRT3 and SIRT5 differently regulate glutamine metabolism with SIRT5 inhibiting glutaminase (GLS) and SIRT3 increasing glutamate dehydrogenase (GDH). Considering the important and interconnected role of glutamine, SIRT3 and SIRT5 for cancer growth and progression, our hypothesis is that a simultaneous modulation of SIRT3 and SIRT5 could represent a valid anti-tumoral strategy. Methods: wt and GLS1-silenced triple negative breast cancer spheroids were treated with 3-TYP, a selective SIRT3 inhibitor, and with MC3138, a new selective SIRT5 activator, both alone and in combination. The effects of such treatments on hypoxia, autophagy and mitophagy markers were determined by immunofluorescence and Western blot. Mitochondria morphology was studied by transmission electron microscopy (TEM) and mitochondrial ROS production by confocal analysis. Results: We observed that 3-TYP+MC3138 treatment decreased the size of spheroids by affecting HIF-1α, c-Myc, glutamine transporter SLC1A5 and autophagy (LC3II) and mitophagy (BNIP3) markers. Moreover, such treatments altered the morphology and conformation of the mitochondria. Finally, we also documented an increase in mitochondria reactive oxygen species (mtROS). Conclusions: The combined inhibition of SIRT3 and activation of SIRT5 greatly reduces the size of spheroids through the inhibition of hypoxic response, which is then followed by the alteration of the autophagic and mitophagic process and the toxic accumulation of mitochondrial ROS, representing a new anti-tumoral strategy. Full article
(This article belongs to the Special Issue Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology—2nd Edition)
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26 pages, 5270 KB  
Article
Gallic Acid and Taurine Attenuate Thiamethoxam-Induced Hepatotoxicity in Rats by Modulating SIRT-1/PGC-1α, NF-κB/iNOS, and p53/Bax/Caspase-3 Pathways
by Sara T. Elazab, Fatmah A. Safhi, Rasha K. Al-Akeel, Raghda H. Deraz, Souvarish Sarkar and Rania Essam Ali Gamal Eldin
Pharmaceuticals 2025, 18(8), 1112; https://doi.org/10.3390/ph18081112 - 25 Jul 2025
Cited by 1 | Viewed by 1706
Abstract
Background/Objectives: Thiamethoxam (TMX) is one of the most extensively utilized insecticides of the neonicotinoid family; however, its application is associated with notable toxic effects on multiple organs of mammals. Our purpose was to explore the potential hepatoprotective effect of taurine (TAU) and/or [...] Read more.
Background/Objectives: Thiamethoxam (TMX) is one of the most extensively utilized insecticides of the neonicotinoid family; however, its application is associated with notable toxic effects on multiple organs of mammals. Our purpose was to explore the potential hepatoprotective effect of taurine (TAU) and/or gallic acid (GA) against TMX-induced liver damage, with an emphasis on their role in regulating SIRT-1/PGC-1α, NF-κB/iNOS, and p53/Bax/caspase-3 pathways. Methods: Rats were assigned to seven groups (n = 6) and gavaged daily for 28 days with saline (control group), TAU at 50 mg/kg, GA at 20 mg/kg, TMX at 78.15 mg/kg, TMX + TAU, TMX + GA, and TMX + TAU + GA. Results: The findings revealed that TAU and/or GA attenuated TMX-induced liver injury, as demonstrated by the restoration of hepatic performance hallmarks and histological structure. TAU and GA mitigated TMX-mediated oxidative stress and boosted the antioxidant defense mechanism by upregulating the transcription levels of SIRT-1, PGC-1α, Nrf2, and HO-1. Moreover, TAU and GA suppressed TMX-associated inflammatory response by increasing IL-10 concentration and lowering the levels of NF-κB, IL-1β, and iNOS; the mRNA levels of NLRP3; and TNF-α immunoexpression. Both compounds, individually or concurrently, exerted an anti-apoptotic effect in TMX-treated rats, evidenced by increased Bcl-2 expression and reduced p53 mRNA level, Bax expression, and caspase-3 concentration. Conclusions: TAU and/or GA may be regarded as promising remedies that can alleviate TMX-induced hepatotoxicity by activating SIRT-1/PGC-1α signaling and abolishing inflammation and apoptosis. Full article
(This article belongs to the Special Issue Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology—2nd Edition)
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Review

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22 pages, 2571 KB  
Review
A Double-Edged Role for SIRT7 in Cancer: Can Anti-Cancer Immunity Tip the Balance?
by Shahriar Tarighi, Zifan Ning, Andrés Gámez-García, Alejandro Vaquero, Thomas Braun and Alessandro Ianni
Pharmaceuticals 2025, 18(12), 1878; https://doi.org/10.3390/ph18121878 - 11 Dec 2025
Viewed by 939
Abstract
Background/Objectives: Sirtuin 7 (SIRT7), a nuclear NAD+-dependent deacylase, plays multifaceted and sometimes opposing roles in tumorigenesis. By preserving chromatin architecture and genome integrity, SIRT7 protects against malignant transformation; however, once cancer is established, it can either sustain or restrain tumor growth [...] Read more.
Background/Objectives: Sirtuin 7 (SIRT7), a nuclear NAD+-dependent deacylase, plays multifaceted and sometimes opposing roles in tumorigenesis. By preserving chromatin architecture and genome integrity, SIRT7 protects against malignant transformation; however, once cancer is established, it can either sustain or restrain tumor growth through context-dependent signaling programs, albeit via largely unknown mechanisms. Recent findings have uncovered an additional—and previously underappreciated—dimension: SIRT7’s capacity to modulate anti-cancer immunity. This review revisits the current understanding of SIRT7 in cancer by emphasizing its emerging immunomodulatory functions and influence on the tumor microenvironment. Methods: We conducted a comprehensive literature review up to October 2025 using the PubMed database to identify both tumor-intrinsic and tumor-extrinsic mechanisms linking SIRT7 to anti-cancer immunity and to relate the established molecular functions of SIRT7—such as its roles in metabolism, genome maintenance, and inflammatory regulation—to immune regulation. Results: SIRT7 directly regulates immune checkpoint expression and T cell metabolic fitness, thereby positioning it as a key node connecting tumor-intrinsic programs with immune surveillance. Moreover, by controlling molecular pathways such as metabolism, genomic stability, and inflammatory responses—both within cancer cells and across other components of the tumor microenvironment—SIRT7 may more broadly influence the immune landscape, orchestrating immune evasion or recognition. Conclusions: Deciphering how SIRT7’s tumor-intrinsic and immunomodulatory functions intersect is essential for anticipating the consequences of its pharmacological targeting in cancer. A deeper understanding of this interplay will enable the rational design of combination strategies that integrate SIRT7 modulation with immunotherapy within a precision medicine framework. Full article
(This article belongs to the Special Issue Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology—2nd Edition)
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38 pages, 1411 KB  
Review
Sirtuins in Women’s Health
by Rasajna Madhusudhana, Abu Hamza, Emily Boyle, Shannon Pollock and Yana Cen
Pharmaceuticals 2025, 18(12), 1859; https://doi.org/10.3390/ph18121859 - 5 Dec 2025
Viewed by 1102
Abstract
The human sirtuins (SIRT1–SIRT7) are NAD+-dependent protein deacylases that orchestrate key cellular events such as metabolism, stress response, DNA repair, and aging. Accumulating evidence highlights their central role in women’s health. This review integrates recent insights into the roles of sirtuins [...] Read more.
The human sirtuins (SIRT1–SIRT7) are NAD+-dependent protein deacylases that orchestrate key cellular events such as metabolism, stress response, DNA repair, and aging. Accumulating evidence highlights their central role in women’s health. This review integrates recent insights into the roles of sirtuins across the female lifespan and their involvement in reproductive, metabolic, oncologic, and age-related disorders. Sirtuins regulate reproductive function, pregnancy outcomes, and hormone-dependent cancers. Their decline with aging contributes to menopausal and metabolic complications. Pharmacological interventions that enhance sirtuin activity, such as NAD+ precursors and SIRT1 activators, show promise in mitigating these conditions. Collectively, understanding the isoform- and tissue-specific roles of sirtuins provides a foundation for developing therapeutics to improve the lifespan and healthspan of women. Full article
(This article belongs to the Special Issue Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology—2nd Edition)
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39 pages, 2446 KB  
Review
Sirtuins as Therapeutic Targets for Treating Cancer, Metabolic Diseases, and Neurodegenerative Diseases
by Maxwell Akantibila and Valerie J. Carabetta
Pharmaceuticals 2025, 18(11), 1723; https://doi.org/10.3390/ph18111723 - 13 Nov 2025
Cited by 1 | Viewed by 1771
Abstract
Sirtuins are NAD+-dependent enzymes that are conserved in all domains of life, including mammals, metazoans, plasmodia, yeast, bacteria, and archaea. In humans, there are seven isoforms (SIRT1 to 7), and they function in cellular homeostasis, aging, DNA repair, survival, metabolism, and [...] Read more.
Sirtuins are NAD+-dependent enzymes that are conserved in all domains of life, including mammals, metazoans, plasmodia, yeast, bacteria, and archaea. In humans, there are seven isoforms (SIRT1 to 7), and they function in cellular homeostasis, aging, DNA repair, survival, metabolism, and stress responses. Recent advances highlight the diverse functions of sirtuins in the pathogenesis and progression of cancer, metabolic diseases, and neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). To date, there is evidence that all seven isoforms contribute to cancer development, while SIRT1-3 and 6 contribute to metabolic and neurodegenerative diseases. Modulators of sirtuin activity are being actively explored to understand their biological and molecular mechanisms and potential for the treatment of various diseases. In this review, we begin with a broad discussion of post-translational modifications, protein deacetylation, and the mechanism of action of sirtuins. Next, we discuss the role of sirtuins in cancer, including inhibitors and activators of sirtuin activity as cancer therapies. In addition, we discuss the relationship of sirtuins to metabolic diseases and as possible treatment targets. Finally, we discuss the role of sirtuins in AD, PD, and HD, and sirtuin modulators for treating neurodegenerative diseases. Full article
(This article belongs to the Special Issue Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology—2nd Edition)
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22 pages, 1314 KB  
Review
The Role of Sirt3 in Kidney Health and Disease
by Ryan S. Azzouz and Liang-Jun Yan
Pharmaceuticals 2025, 18(11), 1668; https://doi.org/10.3390/ph18111668 - 4 Nov 2025
Viewed by 1755
Abstract
Sirtuin 3 (sirt3), a mitochondrial NAD+-dependent deacetylase, is an important enzyme in the maintenance of kidney functions, with critical roles in renal homeostasis, attenuation of oxidative stress, and preservation of mitochondrial homeostasis. This review aims to summarize the current literature on [...] Read more.
Sirtuin 3 (sirt3), a mitochondrial NAD+-dependent deacetylase, is an important enzyme in the maintenance of kidney functions, with critical roles in renal homeostasis, attenuation of oxidative stress, and preservation of mitochondrial homeostasis. This review aims to summarize the current literature on the mechanisms by which sirt3 impacts kidney health and disease, as well as highlight the therapeutic implications of sirt3 targeting. We conducted a PubMed search using the title word “sirt3” and the keyword “kidney” to generate our literature review sources. The animal studies that are explored in this review include cisplatin-induced acute kidney injury, cadmium-induced kidney injury, cecal ligation and puncture (CLP) and lipopolysaccharide-induced sepsis, diabetic kidney fibrosis, high-fat induced kidney disease, and ischemic kidney injury. Increasing evidence points towards a deficiency in sirt3 being an aggravator of mitochondrial dysfunction, promoting abnormal glycolysis, and contributing to the progression of diabetic kidney disease, renal fibrosis, and acute kidney injury. In contrast, pharmacological and dietary activation of sirt3 has been observed to enhance mitochondrial biogenesis, mitigate production of reactive oxygen species (ROS), and preserve the integrity of renal tubular cells under stressful conditions. Collectively, studies point towards sirt3 as a central metabolic and antioxidant regulator within the kidney, and link chronic kidney disease, as well as age-related decline in kidney function, to this enzyme. The conclusion of this review identifies future directions for translational research regarding sirt3 and NAD+-dependent regulation of mitochondrial homeostasis in renal medicine. Full article
(This article belongs to the Special Issue Sirtuins as Novel Biological Targets for Pharmacological Intervention in Physiology and Pathology—2nd Edition)
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