The Promise of Therapeutically Targeting Sirtuins in Lung Fibrosis

Lung fibrosis is a leading cause of death in the industrialized world and is among the most dreaded of pulmonary complications with a progressive yet unpredictable clinical course. The disease is irreversible with early diagnosis and timely prevention being the closest thing to a cure, and lung transplantation is the last resort to save patients that have progressed to advanced stages.

Recent developments in lung fibrosis research have pointed towards a family of enzymes called sirtuins (SIRTs) in regulating the progression of this disease, thereby qualifying them as potential drug targets. However, there is limited literature summarizing the implications of sirtuins on lung fibrosis.

Investigators from India published a comprehensive review on the regulatory role of sirtuins in lung fibrosis. “We tried to delve deeper even into the regulatory roles of under-reported sirtuins on…pathways critical to lung fibrosis and indicate plausible implications therein,” said the authors. The authors proposed that there are ample opportunities to conduct biomedical exploratory studies to come up with sirtuin-based novel therapeutic strategies against lung fibrosis.

Sirtuins are implicated in age-related degenerative and inflammatory disorders as well as in almost all types of organ fibrosis. Four of the seven sirtuins (SIRT1, SIRT3, SIRT6, and SIRT7) are documented to be protective in cardiovascular, pulmonary, and metabolic diseases including fibrosis. However, the functional roles of the remaining sirtuins (SIRT2, SIRT4, and SIRT5) in lung diseases remain elusive.

Overall, sirtuins appear to exert protective action in lung fibrosis. Although no reports as of now precisely point out the roles of SIRT4 and SIRT5 in lung fibrosis, protective effects of these sirtuins may be presumed owing to their beneficial effect on mitochondria, the powerhouses of the cell. A clear understanding of these unknown aspects of sirtuin biology is expected to identify new drug targets in lung fibrosis. Regarding SIRT4 and SIRT5, scientists advocate for studies to identify their role in lung fibrosis.

The only sirtuin that does not appear to exert protective action in lung fibrosis is SIRT2, which may show pro-fibrotic action given its pro-inflammatory effects observed in asthma. From available data on the negative association of SIRT2 with asthma, it may be considered that inhibiting SIRT2 could prove beneficial in the fibrotic setting as well.

An intriguing question regarding sirtuin-induced regulation of lung fibrosis is how sirtuins are activated and regulated. Apart from SIRT1 and SIRT3, the activation of SIRT 6 and SIRT7 is also expected to prevent lung fibrosis owing to the regulatory action of these sirtuins. In terms of therapeutic modulation, targeting SIRT1, SIRT3, SIRT6, and SIRT7 appears promising because laboratory studies in animals and cell lines along with data from patients with lung fibrosis strongly indicate the protective roles of these sirtuins.

The authors also discussed potential therapeutic options targeting sirtuins using synthetic- and plant-derived compounds that can help researchers to design new-generation cheap, non-toxic sirtuin-based drugs against lung fibrosis. In this regard, honokiol, the natural SIRT3 inducer obtained from Magnolia officinalis bark extract, and resveratrol, a natural SIRT1 inducer found in grapes, have been found to protect against lung fibrosis in mice. Owing to the poor bioavailability of resveratrol, various formulations with improved bioavailability have been developed and commercialized as dietary supplements, such as Longevinex®, resVida®, and SRT501. These formulations are already commercially available for human usage but are not approved by the U.S. Food and Drug Administration as drugs because the FDA does not strictly regulate herbs and dietary supplements.

While natural plant-derived compounds have already acquired the limelight for potential therapeutics, the synthesis of small molecule modulators of sirtuins is a promising area of drug development for lung fibrosis. The focus should always be levied on strategies that can enrich sirtuin inducers from indigenous plant sources or bulk-scale production of synthetic activators, which can lead to the production of cheaper effective drugs.

While most of the potential therapeutic compounds are tested in the preclinical studies using experimental models, some have been also tested in clinical trials for different diseases. Therefore, clinical trials of these compounds in lung fibrosis are crucial before humans can utilize them for disease-mitigating purposes.

“In summary, the role of sirtuins in regulating pulmonary fibrosis is immense and unambiguous,” said the authors. “It depends on us as to what extent we can rationally exploit these marvelous therapeutic targets to overcome this deadly disease.”