Are statins interferon’s best friends? Mechanistic insights

TO THE EDITOR:

In a previous issue of Blood Advances, Davidsen et al¹ reported the results from a single-center retrospective cohort study providing evidence that concurrent statin therapy may enhance the efficacy of interferon alfa 2 (IFN-α2) in patients with BCR::ABL1-negative myeloproliferative neoplasms (MPNs).

This relevant clinical observation was drawn from a study cohort including polycythemia vera (PV), essential thrombocythemia, and myelofibrosis cases, for a total of 129 patients, divided into 4 groups according to statin use (statin users vs nonusers) and type of cytoreductive therapy (IFN-α2 vs hydroxyurea), for an overall observation period of 11 years (2011-2022). Data show that among IFN-α2–treated patients, statin users achieved a higher complete hematologic response rate in a shorter period of time, and more durable responses, compared to statin nonusers. Of note, statin users required lower doses of IFN-α2 to achieve and maintain hematologic response. In line with this, the use of statins in IFN-α2–treated patients was significantly associated with a reduction of the JAK2^V617F allele burden. Furthermore, and most importantly, these effects were not seen in hydroxyurea-treated patients, where no difference in terms of hematologic and molecular response rates were detected among statin users vs nonusers.

The authors acknowledge that a potential synergistic effect between IFN-α2 and statins could be mediated by the anti-inflammatory proprieties of statins. Given the lack of significant hematologic and molecular improvement observed in the hydroxyurea-treated group, it is possible that the clinical benefit associated with the IFN-α2 plus statin combination could involve the modulation of specific common molecular pathways, within the malignant clone.

Statin repurposing as a therapy for MPNs on the basis of their anti-inflammatory activity has been discussed by Hasselbalch² in a comprehensive review, published recently in the same journal. Notably, although Kristensen et al³ suggest that statins may protect from MPN development, Leiva et al⁴ failed to identify a link between 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor therapy and improvements in progression-free survival, or all-cause mortality, among all 3 MPN subtypes. Surprisingly, statin use did not ameliorate cardiovascular nor mortality-related outcomes in the burned-out, myelofibrotic stage of the disease.⁴

In agreement with Leiva et al,^4,5 we can infer that the efficacy of statins’ anti-inflammatory proprieties could be maximal in individuals without an overt (onco-)inflammatory condition, as in the case of individuals bearing mutations associated with clonal hematopoiesis of indeterminate potential,^2,3 atherosclerotic plaques,^2,6 or abdominal aneurysms.^2,7 Instead, in “florid-phase” MPNs, as PV and essential thrombocythemia, statins might effectively curb the “circulating wound” (well described by Lucchesi et al),⁸ but are unlikely to exert any significant anti-inflammatory or cytoreductive activity on the inflamed bone marrow microenvironment.⁴

Therefore, we hypothesize that the benefits observed by Davidsen et al¹ may derive from specific, synergistic interactions between the 2 agents, rather than a broader, generic statins’ anti-inflammatory activity. Hence, as also suggested by Hasselbalch,² statins could indeed be helpful in combination therapy regimens. Building on current evidence, we highlight potential molecular mechanisms underlying the synergy between IFN-α and statins, summarized in Figure 1.

Figure 1.

Summary of possible pathways underlying apparent clinical benefit of IFN-α plus statins compared to IFN-α monotherapy. This figure summarizes how IFN-α and statin-mediated signaling disruptions intersect and cooperate in determining cytostatic and cytoreductive effects. IFN-α receptor signaling activates (1) signal transducer and activator of transcription 1 (STAT1) and STAT2, which heterodimerize or homodimerize and translocate to the nucleus; (2) other STAT-independent mediators (collectively summarized as “non-STAT signaling”), in part responsible for downstream p38 activation. p38 is physiologically activated by cytokines, such as IFN-α, and other inflammatory, stress-related, or stress-unrelated signals, and may induce either cell death or cell survival in a context-dependent fashion. Non-STAT signaling may also induce ROCK activation, which negatively regulates p38. ROCKs may also be activated by RhoGTPases possibly cooperating in this resistance mechanism. Statins inhibit RhoGTPases by preventing their prenylation, likely contrasting ROCK-mediated resistance to IFN-α. Although in normal cells DUSP-1 protects the cell from stress-induced cell death by dampening p38 signaling, in JAK2-mutant cells DUSP-1 is aberrantly activated by JAK2 dysregulated signaling and can protect these cells from the inflamed MPN bone marrow microenvironment. Furthermore, the combined inhibition of STAT3 signaling by statins and IFN-α may more effectively target a key prosurvival, proproliferative pathway hijacked by MPN cells than either agent alone. HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; IFNAR1/2, interferon-α receptor 1/2; JAK1, Janus kinase 1; JAK2VF, V617F-mutant Janus kinase 2; MPL, myeloproliferative leukemia protein; P, phosphate; TYK2, tyrosine kinase 2. Figure created with biorender.com. Cerreto GM. (2026) https://biorender.com/f36og3s.

IFN-α signals through a dimeric receptor. Its subunits, namely IFN-α receptor 1 and 2, can respectively bind to TYK2 and JAK1. The interaction of IFN-α with its receptor activates STAT1 and STAT2, resulting in the transcription of genes, which are ultimately responsible for the acquisition of DNA damage and apoptosis.⁹ IFN-α receptor signaling can also induce p38 MAPK phosphorylation via non-STAT pathways.^10,11

p38 are serine/threonine-specific protein kinases, part of the MAPK superfamily, which are activated by stress signals and inflammatory cytokines, but also by stress-unrelated cues that regulate proliferation, differentiation, and survival. p38 signaling displays a marked context dependency, exerting either tumor-suppressive or tumor-promoting functions, orchestrating either cell survival or death.^12,13 Specifically, excessive p38 activation leads to cellular senescence and/or apoptosis.¹⁴

In MPNs, its antiproliferative effects were first demonstrated in chronic myeloid leukemia,¹⁰ and more recently in JAK2^V617F mutant cells.^11,15 In 2010, Lu et al¹⁵ first demonstrated that pegylated–IFN-α2a was capable to reduce proliferation and increase the apoptosis rate of PV CD34⁺ cells, via p38 phosphoactivation; p38 specific pharmacologic inhibition reversed these effects.

More recently, Saleiro et al¹¹ showed that p38 MAPK activation by phospho-ULK1 is essential for IFN-α–mediated suppression of malignant erythroid precursors in MPNs. In addition, they also showed that IFN-α induces activation of Rho-associated coiled-coil–containing kinase (ROCK) 1 and 2, triggering a negative feedback that dampens IFN-α responses.

Because ROCK1 and 2 are overexpressed in MPNs, and their inhibition enhances IFN-α antineoplastic effects, ROCK-targeting may improve IFN-α therapeutic efficacy. In this context, it is worth noting that ROCK activators include RhoGTPases,¹⁶ whose prenylation, membrane localization, and function depend on cholesterol biosynthesis intermediates (CBIs).^2,16 Therefore, statins, by reducing the production of CBIs, may help to overcome ROCK-mediated IFN-α resistance.

Additionally, p38 signaling is regulated by dual-specificity protein phosphatase-1 (DUSP-1), which protects cells from accumulating DNA damage by buffering its activity. Stetka et al¹⁴ demonstrated DUSP-1 overexpression in JAK2^V617F-mutant CD34⁺ progenitor-enriched cultures from patients with PV, and that its inhibition, in both JAK2^V617F-mutant and CRISPR/Cas9 JAK2^WT-edited human erythroleukemia cells, increased p38 phosphorylation. This indicates a role for DUSP-1 in limiting stress-induced p38 signaling in PV progenitors, thereby preventing robust activation of cell cycle checkpoints and cellular senescence. IFN-α may act by overriding this protective pathway, enhancing p38 phosphoactivation and eventually leading to increased apoptosis and reduced colony formation in vitro.

Overall, we propose that the synergy between IFN-α2 and statins in PV (and MPNs in general) progenitors may rely on 2 distinct yet potentially cooperative mechanisms, involving the p38 MAPK and RhoGTPase-ROCK pathways, respectively.

As potential limits to this hypothesis, we need to acknowledge that the effects of statins on MAPKs remain subject to debate, as they appear to be drug-specific and context-dependent. For example, only fluvastatin (and not atorvastatin or simvastatin), was capable of inducing apoptosis in lymphoma cells by increasing intracellular reactive oxygen species generation, p38 activation, and suppressing Ak strain transforming and extracellular signal-regulated kinase, via CBI depletion.¹⁷ Nonetheless, in other reports, fluvastatin downregulated p38 activity,¹⁸ whereas simvastatin activated p38 by RhoA inhibition.¹⁹

Moreover, potential interactions between statins and IFN-α could involve other mediators, such as STAT3. STAT3 activation is a critical driver of clonal proliferation in MPNs, fueled by dysregulated JAK2 signaling.²⁰ It has been pinpointed as a key target of IFN-α in MPNs and other disease models,^21,22 and, notably, can also be targeted by statins, which inhibit its phosphorylation and nuclear translocation.²³

In conclusion, IFN-α is emerging as a promising agent for achieving disease-modification. Notwithstanding its clinical benefits, IFN-α is burdensome due to tolerability and discontinuation rates; moreover, its efficacy becomes apparent only after prolonged administration and varies according to disease subtype, stage, and driver mutations. Statins may represent a valuable adjunct to overcome these limitations by reducing circulating inflammation and by sensitizing malignant cells to IFN-α.

Future studies directed at a better characterization of the mechanisms underlying the effects of IFN-α and statins in different clinical scenarios, particularly in JAK2^V617F-mutant clonal hematopoiesis of indeterminate potential, which is associated with the highest cardiovascular risk, as well as in “florid” and “spent” phases of MPNs, are eagerly awaited. Such investigations will be crucial to inform personalized indications for statin use in MPN management.

Conflict-of-interest disclosure: E.M. reports honoraria from or advisory board membership for Novartis, GSK, and AOP Health. The remaining authors declare no competing financial interests.