Coumarins as modulators of autophagy and PI3K/mTOR signaling: implications for next-generation cancer therapies

Abstract

Background

Aberrant regulation of autophagy and persistent activation of the phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) signaling axis are recognized hallmarks of cancer progression, therapeutic resistance, and disease relapse. Coumarins, a chemically diverse class of natural and synthetic benzopyranone derivatives, have recently emerged as promising modulators of both autophagy and PI3K/mTOR signaling, positioning them as attractive candidates for next-generation anticancer strategies. Aim: This review critically examines current evidence on the ability of coumarin derivatives to regulate autophagy and PI3K/mTOR signaling in cancer, with emphasis on their mechanistic intersections, therapeutic implications, and translational potential.

Methods

A structured and integrative analysis of preclinical studies was conducted using major scientific databases, including PubMed, Scopus, and Web of Science. Relevant articles were identified using combinations of keywords such as “coumarins”, “autophagy”, “PI3K/mTOR”, and “cancer”. Only peer-reviewed studies written in English and reporting data from cellular or animal cancer models were included. Mechanistic evidence related to autophagy induction or inhibition, modulation of the PI3K/mTOR pathway, pharmacokinetic properties, safety considerations, and combination therapy strategies was systematically evaluated.

Results

Accumulating evidence demonstrates that coumarins can either induce or inhibit autophagic flux in a context-dependent manner, often through direct or indirect modulation of PI3K/mTOR signaling. These dual actions influence cancer cell survival, apoptosis, senescence, and sensitivity to chemotherapy. Several coumarins exhibit multitarget activity, addressing therapy resistance while maintaining favorable safety profiles. Emerging data further support their use in rational combination strategies and patient-stratified therapeutic approaches.

Conclusion

Coumarins represent versatile molecular scaffolds capable of fine-tuning autophagy and PI3K/mTOR signaling in cancer. A deeper mechanistic understanding, alongside optimization of pharmacokinetics and patient stratification, will be essential for translating coumarin-based modulators into clinically effective anticancer therapies.

Graphical abstract

Highlights

• •Coumarins act as context-dependent modulators of autophagy in cancer.
• •PI3K/mTOR signaling represents a central target underlying their anticancer activity.
• •Dual regulation of autophagy influences cancer cell survival, death, and therapeutic response.
• •Coumarins exhibit multitarget effects beyond PI3K/mTOR, including MAPK and NF-κB pathways.
• •Rational design and combination strategies may enhance efficacy and overcome chemoresistance.
• •Further mechanistic insights are required to support clinical translation of coumarin-based therapies.

1. Introduction

Coumarins constitute a widely distributed and extensively investigated class of natural compounds, and accumulating evidence now identifies these structurally diverse molecules as important modulators of autophagy and the PI3K/mTOR signaling axis [1]. Aberrant activation of the PI3K/mTOR pathway is increasingly recognized as a defining feature of many cancers and a major driver of therapeutic resistance, underscoring the need to clarify how coumarins influence this signaling network [2]. Elucidating these mechanisms may open new avenues for the development of next-generation anticancer agents. Compounds derived from, or inspired by, coumarins possess distinct advantages that stem from their evolutionary optimization and chemical versatility [3]. Advances in chemical synthesis, molecular pharmacology, and systems biology now allow the identification of drug-responsive signaling circuits, enabling rational target selection and focused preclinical evaluation [4]. Within this context, integrating coumarins into well-defined therapeutic frameworks represents a promising strategy for anticancer drug discovery [5].

Autophagy, a tightly regulated cellular recycling process, plays a multifaceted role in cancer by either supporting tumor cell survival or promoting tumor suppression, depending on cellular context and disease stage. This process also critically influences tumor responses to chemotherapy, radiotherapy, and immunotherapy [6]. The phosphoinositide 3-kinase (PI3K)–protein kinase B (AKT)–mechanistic target of rapamycin (mTOR) signaling cascade serves as a central oncogenic pathway and a key negative regulator of autophagy. Consequently, pharmacological inhibition of PI3K, mTOR, or both has become an established therapeutic strategy across multiple malignancies [7]. However, the frequent development of resistance to these agents highlights the urgent need for alternative or complementary approaches capable of addressing resistant and molecularly distinct tumor subtypes [8]. Notably, preclinical evidence demonstrates that both natural and synthetic coumarins can directly influence autophagic flux and PI3K/mTOR signaling, thereby supporting their potential utility in anticancer drug development and rational combination therapies [9].

Among the multiple oncogenic pathways influenced by coumarins, the PI3K/mTOR signaling axis was selected as a primary focus of this review due to its central role in integrating growth signals with autophagy regulation. Unlike other pathways such as MAPK or NF-κB, PI3K/mTOR directly governs key steps in autophagic initiation and flux, making it a critical determinant of cancer cell survival and therapeutic resistance. This functional intersection provides a strong mechanistic rationale for examining coumarins within the context of PI3K/mTOR-driven autophagy modulation [10].

1.1. Coumarins: chemical diversity and pharmacological relevance

Coumarins constitute a structurally diverse family of plant-derived secondary metabolites, predominantly biosynthesized in the roots and stems of numerous plant species. Although their biosynthesis is primarily associated with higher plants, coumarins are also encountered across a broad range of natural sources, including fungi and microorganisms, frequently occurring as glycosylated derivatives [11]. Structural diversity within this class arises from modifications of the coumarin scaffold as well as substitutions at key positions (C-4, C-5, C-6, and C-3), giving rise to a wide spectrum of compounds with distinct physicochemical and biological properties [12]. Unlike other major classes of natural products such as flavonoids or alkaloids, which display extensive distribution across biological kingdoms, coumarins show a more restricted and characteristic occurrence, making them valuable chemotaxonomic markers at the genus and species levels [13]. Beyond their taxonomic relevance, coumarins have attracted considerable pharmacological interest, particularly for their therapeutic potential in cancer. Collectively, these features justify a more integrated evaluation of coumarins, especially in the context of their interactions with critical cellular signaling networks, including autophagy and the PI3K/mTOR pathway [14]. As our understanding of the molecular determinants of treatment response continues to expand, therapeutic strategies increasingly aim to exploit vulnerabilities within these regulatory circuits. In this regard, emerging preclinical evidence indicates that several natural compounds, including coumarins, can influence cancer cell survival by modulating autophagy and PI3K-dependent signaling [15]. A focused and mechanistic assessment of these effects may therefore provide a strong foundation for the rational development of coumarin-based agents as novel anticancer therapeutics.

Recent reviews have extensively described the general pharmacological properties of coumarins in cancer [16,17]. In contrast, the present review provides a focused and integrative perspective on the mechanistic interplay between autophagy regulation and PI3K/mTOR signaling. By specifically addressing how coumarins modulate these interconnected pathways at multiple regulatory levels, this work aims to bridge a critical gap between descriptive pharmacology and mechanism-driven therapeutic design.

1.2. Autophagy in cancer: Dual roles and therapeutic implications

Autophagy, as illustrated in [Fig. 1], helps maintain cellular homeostasis through the turnover of damaged organelles, protein aggregates and invading pathogens. Under stressed conditions, such as nutrient deprivation (see [Fig. 2]) or hypoxia, induction of this catabolic process derives cellular survival advantages; however, loss of functional autophagy potentiates cellular susceptibility to these stresses [18]. For this reason, the role of autophagy in cancer is complex because loss of autophagy and constitutive autophagy induction may be linked to tumor progression, increased aggressiveness and resistance to anticancer therapies. Therapeutically targeting autophagy is seen as an attractive strategy and strategies involving autophagy modulators are being developed [19]. Coumarins are important scaffold structures in medicinal chemistry, with diverse biological activity. The influence of coumarin derivatives on cancer has been the focus of research efforts, highlighting their ability to modulate autophagy, an important process also targeted by the PI3K pathway [20]. This is an essential growth signaling pathway that promotes cellular proliferation and metabolism. Aberrant activation of the PI3K pathway contributes to the development of malignancy and causes resistance to some anticancer therapies [21].

Fig. 1.

An illustration of autophagy working steps.

Fig. 2.

Cancer cell metabolism in nutrient-deprived conditions.

Whether coumarins induce or inhibit autophagy flux can determine their mode of action during cancer therapy. Different coumarin derivatives modulate PI3K/mTOR pathway activity, suggestive of a direct role in cancer treatment [22]. In this context, coumarins are undergoing evaluation for therapeutic application and their incorporation in hybrid molecules is being considered [23]. Preclinical data support the development of autotphagy-modulating coumarin derivatives with anticancer activity and pharmacological safety [24]. These findings suggest that coumarins warrant further investigation as modulating agents of the PI3K/mTOR pathway to aid development of next-generation therapies.

Certain coumarin derivatives such as esculetin and scopoletin have been reported to induce cytoprotective autophagy through ROS-mediated mechanisms, thereby enhancing cellular adaptation to stress conditions [25]. In contrast, compounds such as osthole and aurapten have been associated with excessive or dysregulated autophagy that contributes to autophagic cell death and tumor suppression [26]. These findings highlight the context-dependent nature of coumarin-mediated autophagy and underscore the importance of distinguishing between cytoprotective and cytotoxic outcomes in different cancer models.

1.3. PI3K/mTOR signaling in oncogenesis and therapy resistance

The PI3K/mTOR signaling axis, that displayed in [Fig. 3], plays a central role in cancer progression and therapeutic resistance, in part through its tight regulation of autophagy [27]. Activation of this pathway leads to downstream engagement of AKT and mTOR complexes, particularly mTORC1, which functions as a key negative regulator of autophagy [28]. By phosphorylating ULK1, mTORC1 suppresses autophagy initiation, thereby promoting anabolic growth and tumor cell survival [29]. Persistent activation of PI3K/mTOR signaling, a common feature of many malignancies, is therefore closely associated with reduced autophagic activity and resistance to anticancer therapies [30].

Fig. 3.

The PI3K/mTOR pathway and its cellular components and effects.

Beyond autophagy initiation, PI3K/mTOR signaling also influences autophagic flux. Sustained pathway activation can impair the completion of autophagy, enabling cancer cells to exploit this process as an adaptive survival mechanism under therapeutic stress [31]. In this context, modulation of PI3K/mTOR-dependent autophagy represents a critical determinant of treatment response. Notably, several coumarin derivatives have been shown to interfere with this pathway, either directly or indirectly, leading to altered autophagic activity and enhanced anticancer effects [32]. These observations support the rationale for targeting PI3K/mTOR–autophagy crosstalk using coumarin-based strategies, particularly in combination with other therapeutic agents [33].

1.4. Mechanistic intersections: How coumarins influence autophagy

The available evidence supports a conceptual framework in which coumarin-based compounds can be strategically incorporated into emerging anticancer therapies [34]. From a pharmacotherapeutic perspective, coumarins modulate autophagy at several critical regulatory nodes rather than acting through a single linear mechanism [35]. A deeper and more nuanced understanding of the molecular determinants that shape cellular responses to coumarins is therefore essential for the rational development of personalized treatment strategies.

Under conditions of cellular stress, coumarins may trigger cytoprotective autophagy in cancer cells, enabling their use at therapeutically relevant doses as adjuvant agents [36]. The biological outcome of such interventions is strongly influenced by the expression levels or functional status of key autophagy-related regulators, including TSC2, BECN1, SHMT2, and p62. Targeted modulation of these molecules could thus provide a means to fine-tune the efficacy of coumarin-based therapies [37]. In contrast, deliberately enhancing autophagic flux can also sensitize tumor cells to coumarin-induced cytotoxicity. This concept is illustrated by combination strategies involving autophagy-promoting agents such as metformin [38], resveratrol [39], or curcumin [40], which elevate BECN1 expression, as well as by the use of BECN1-mimetic inhibitors of mTORC1 [41].

In other contexts, specific coumarin derivatives suppress autophagy under both basal and stress-induced conditions. This inhibition frequently occurs at late stages of the autophagic pathway, often due to disrupted autophagosome–lysosome fusion or reduced lysosomal enzymatic activity [42]. Several natural and synthetic coumarins potently interfere with the PTEN–PI3K–AKT signaling axis, and all reported coumarin-derived autophagy inhibitors attenuate PI3K–p70S6K signaling [43]. Moreover, accumulating evidence indicates that the ULK1 complex, a central initiator of early autophagy, is also negatively regulated by these compounds [44] [Fig. 4. Collectively, these findings underscore the capacity of coumarins to either activate or suppress autophagy at multiple levels, highlighting their versatility as modulators of cancer cell survival and death pathways.

Fig. 4.

Multilevel regulation of autophagy by coumarins through PI3K/mTOR–ULK1 signaling nodes.

1.4.1. Autophagy induction by coumarins

Substantial experimental evidence indicates that several coumarin derivatives are capable of activating autophagy across diverse cellular systems through multiple, context-dependent mechanisms [45], as reported in [Table 1]. One of the most frequently reported pathways involves the modulation of cellular redox status. In this regard, coumarins have been shown to promote reactive oxygen species (ROS) accumulation, leading to autophagy induction under both normoxic and hypoxic conditions [46]. Hypoxia-associated autophagy has been linked to neuroprotective signaling that mitigates hypoxia-induced neuronal damage, whereas ROS-driven autophagy has been correlated with improved therapeutic responses in drug-resistant gastric cancer models [47].

Table 1.

Structurally confirmed coumarin derivatives reported to induce autophagy.

Coumarin derivative	Autophagy-related mechanism of action	Biomedical effects/cellular context	Ref.
Esculetin (6,7-dihydroxycoumarin)	ROS-mediated activation of autophagy under normoxic and hypoxic conditions	Neuroprotection against hypoxia-induced neuronal injury and cytoprotective autophagy	[48]
Scopoletin (6-methoxy-7-hydroxycoumarin)	ROS accumulation leading to enhanced autophagic flux	Increased sensitivity of drug-resistant gastric cancer cells	[49]
Osthole (7-methoxy-8-prenylcoumarin)	Modulation of AMPK signaling; ER stress–induced autophagy via BIP/ATF4/CHOP pathway	Autophagy induction and autophagic cell death in HNEK and HEK293 cells	[50]
Psoralen (7H-Furo[3,2-g][1]benzopyran-7-one)	Ca+2 influx–mediated activation of CAMKK2 and downstream AMPK signaling	Enhancement of CaCl2-induced autophagy and stress-adaptive responses	[51]
Bergapten (5-methoxypsoralen)	Ca+2–CAMKK2–AMPK pathway–dependent autophagy induction	Cytoprotective and anticancer-related autophagy	[52]
Xanthotoxin (8-methoxypsoralen)	Oxidative stress–associated AMPK activation linked to autophagy	Autophagy-associated anticancer effects	[53]
Decursin (angular pyranocoumarin)	Activation of Nrf2-dependent antioxidant signaling coupled to autophagy regulation	Cytoprotective and anticancer effects	[54]
Decursinol angelate (pyranocoumarin ester)	Nrf2-driven redox signaling with downstream autophagy induction	Stress-adaptive and chemopreventive effects	[55]
Aurapten (7-geranyloxycoumarin)	Transcriptional repression of mTOR-related signaling and chromatin remodeling	Suppression of oncogenic signaling via autophagy	[56]
Imperatorin (8-isoamylenoxypsoralen)	AMPK activation with downstream autophagy induction	Anticancer and neuroprotective effects	[57]
Herniarin (7-methoxycoumarin)	ROS-sensitive autophagy modulation	Anti-inflammatory and cytoprotective activity	[58]

1.4.2. Autophagy inhibition and flux blockade by coumarins

As summarized in [Table 2], multiple coumarin derivatives have been reported to suppress autophagic flux in cancer cells, either through direct interference with the autophagy machinery or indirectly as a downstream consequence of inhibiting the PI3K/mTOR signaling axis [59]. A hallmark of this effect is the accumulation of autophagic vacuoles, which signifies a blockade in autophagic flux rather than a failure of autophagosome formation. Importantly, the persistence of intact autophagic structures indicates that the core autophagic machinery remains operational; however, the failure of sequestered organelles to undergo degradation points to impaired lysosomal activity [60]. This observation aligns with evidence that certain coumarins promote lysosomal membrane permeabilization, ultimately triggering cell death pathways [61]. Comparable inhibition of autophagic flux downstream of autophagosome formation has been described in cells treated with farnesylthiosalicylic acid or the PI3K inhibitor LY294002 [62]. In these contexts, autophagy blockade is accompanied by the accumulation of C/EBP homologous protein (CHOP), a marker of endoplasmic reticulum (ER) stress, which closely correlates with the initiation of cell death and can be abrogated by CHOP-specific siRNA [63]. Collectively, these findings suggest that autophagic flux inhibition induced by such compounds is mechanistically linked to ER stress signaling.

Table 2.

Coumarin derivatives inhibiting autophagic flux in cancer therapy.

Coumarin derivative	Autophagy-related mechanism of action	Biomedical effects/cellular context	Ref.
Esculetin	Blocks autophagic flux at lysosomal stage; ER stress and CHOP induction	Promotes apoptosis in autophagy-dependent cancer cells	[64]
Daphnetin (7,8-dihydroxycoumarin	Suppresses PI3K/AKT/mTOR signaling causing incomplete autophagy	Induces growth arrest and apoptotic death in solid tumors	[65]
Auraptene	Epigenetic and transcriptional repression of autophagy-related genes	Inhibits proliferation and stress adaptation in cancer cells	[66]
Scopoletin	Induces lysosomal membrane permeabilization	Triggers lysosome-mediated death in resistant tumors	[67]
Umbelliferone (7-hydroxycoumarin)	Inhibits late-stage autophagy via lysosomal enzyme suppression	Enhances chemosensitivity and oxidative stress response	[68]
Farnesylated coumarins	Blocks autophagic flux downstream of autophagosome formation	Enhances ER stress-mediated apoptosis	[69]
Coumarin–DAPT nanoformulations	Dual γ-secretase and autophagy flux inhibition	Potentiates cytotoxicity in Notch-driven cancers	[70]
Synthetic hydroxy-coumarins	Inhibit autophagic degradation without blocking initiation	Promote non-apoptotic cell death	[71]
Warfarin analogs	Disrupt autophagy–lysosome function independent of anticoagulation	Suppress tumor growth with reduced toxicity	[72]
4-Hydroxycoumarin derivatives	Impair autophagosome maturation and lysosomal fusion	Induce metabolic stress and cell cycle arrest	[73]
Osthole	Modulates PI3K/AKT/mTOR–autophagy crosstalk	Inhibits tumor growth and metastasis	[74]
Isopimpinellin (5,8-dimethoxypsoralen)	Suppresses autophagic turnover under nutrient deprivation	Enhances chemosensitivity	[75]
Bergamottin (5-geranoxypsoralen)	Disrupts lysosomal acidification	Induces oxidative stress and apoptosis	[76]
Dicoumarol derivatives	Interfere with NAD(P)H-dependent autophagy regulation	Promote mitochondrial dysfunction	[77]
Coumarin-based hybrids	Simultaneous inhibition of oncogenic signaling and autophagic flux	Overcome drug resistance in cancer cells	[78]

It is important to note that these effects may arise through both direct and indirect mechanisms. In some cases, coumarins appear to directly impair lysosomal function or autophagosome–lysosome fusion, whereas in other contexts the observed inhibition of autophagic flux may represent a secondary response to cellular stress, including oxidative stress or ER stress signaling. Distinguishing between these mechanisms remains an important area for further investigation [79].

1.4.3. Modulation of PI3K/mTOR pathway by coumarins

Dysregulation of the PI3K/mTOR signaling axis is a defining molecular feature of many human malignancies. PI3K functions as a central signaling hub downstream of receptor tyrosine kinases activated by growth factors, hormones, and other extracellular cues. Once engaged, this pathway stimulates cell growth and metabolic reprogramming primarily through Akt and mTORC1, thereby supporting protein synthesis, ribosome biogenesis, glycolysis, and mitochondrial function [80]. Persistent or excessive mTORC1 activity not only fuels tumor development but also contributes to therapeutic resistance. In parallel, autophagy is largely controlled by mTORC1 signaling. Suppression of basal autophagy has therefore been associated with enhanced tumor survival and progression [81].

Aberrant activation of the PI3K/mTOR pathway promotes tumor initiation, accelerates disease progression, and diminishes responsiveness to anticancer therapies. Accumulating evidence indicates that coumarin derivatives can attenuate hyperactivated PI3K and mTOR signaling at multiple regulatory nodes [82], as shown in [Fig. 5]. For example, a coumarin–peptide conjugate has been shown to indirectly suppress PI3K–Akt signaling in breast cancer cell models, highlighting the capacity of coumarins to modulate oncogenic signaling cascades. Such effects may help address the therapeutic challenges posed by sustained PI3K/mTOR activation [83]. Importantly, restoration of autophagic flux alongside PI3K inhibition has been linked to the reversal of drug resistance, including resistance to imatinib in cancer cells characterized by concurrent PI3K hyperactivation and defective autophagy [84]. Moreover, in glioblastoma models driven by Jun–Notch signaling, natural coumarin derivatives have been reported to downregulate PI3K/Akt/mTOR and ERK pathways, resulting in impaired tumorigenic potential and broad anticancer effects [85]. Together, these findings underscore the potential of coumarin-based modulators as multifunctional agents targeting interconnected survival pathways in cancer.

Fig. 5.

Anticancer potential of coumarins through modulation of the hyperactive PI3K/mTOR pathway.

1.5. Preclinical evidence supporting coumarin-based strategies

An integrated perspective on coumarin pharmacology supports pro-autophagic modulation as a promising approach in cancer therapy, particularly when attention is given to key signaling intersections that shape therapeutic outcomes. By fine-tuning autophagic pathways, coumarins address several unmet challenges in oncology and offer opportunities to enhance or repurpose existing anticancer agents [86]. Accumulating preclinical evidence highlights their broad anticancer potential alongside additional health-promoting effects, positioning coumarins as attractive lead scaffolds for future drug development [87]. In several experimental models, disruption of the pro-survival arm of autophagy has been shown to contribute to the anticancer activity of maleimide derivatives and structurally related compounds [88]. Specific coumarins bearing additional oxygenated substituents and a 3-phenyl moiety promote autophagosome formation, an effect that may be linked to enhanced lysosomal biogenesis, activation of endocytic–autophagic trafficking, and acidification of lysosomal compartments [89]. In a complementary anticancer context, 4-methylcoumarin potentiates the efficacy of paclitaxel in breast cancer cells by promoting apoptosis, inducing autophagic phenotypes, and suppressing MDR1 expression [90].

1.6. Pharmacokinetic and safety considerations for coumarin-derived therapies

Although many coumarins are traditionally limited by poor aqueous solubility, low oral bioavailability, and relatively rapid systemic clearance, several studies demonstrate that these pharmacokinetic drawbacks can be mitigated through rational structural modification [91]. For example, deacetylated and demethoxylated derivatives of 3-piperidyl-4H-chromen-4-one have achieved oral bioavailability values of approximately 29%, while exhibiting low cytotoxicity (LC₅₀ > 100 μM) in THP-1 cells [92]. In parallel, newly developed phosphoramidate- and oligosaccharide-linked coumarin derivatives have shown potent anti-HIV-1 activity accompanied by minimal toxicity in Molt-4 cells. Among these, S-(β-d-glucosyl)-β,β-dimethyl-3,4,5-trihydroxy-6-coumarinyl propionamide hemihydrochloride has emerged as a promising candidate with favorable pharmacokinetic attributes [93].

Elucidating the mechanisms of action of such emerging coumarin scaffolds also informs practical synthetic strategies, as illustrated by studies on 3-(salicylideneamino)benzoic acid derivatives [94]. Structure–toxicity relationship analyses have further identified specific substituent patterns that reliably predict low Tox21-associated toxicity across multiple compounds, while advanced in silico models suggest that potential adverse effects may primarily involve cancer-related pathways, immune regulation, and core cellular functions [95]. Importantly, for certain naturally occurring coumarins—such as those derived from the roots of the North American plant Hydrocolicium rusifolium—human consumption within customary dietary ranges is associated with reduced toxicity risk [96]. Moreover, several natural–synthetic hybrid coumarins display good stability across a broad pH range while retaining antioxidant activity, supporting their potential development as nutraceuticals or functional food supplements [97].

Despite these advances, several challenges remain for the clinical translation of coumarin-based therapeutics. Common limitations include poor aqueous solubility, rapid metabolic clearance, and variable bioavailability. Strategies such as nanoformulation, prodrug design, and structural modification have shown promise in overcoming these barriers; however, further systematic evaluation is required to optimize pharmacokinetic profiles and ensure consistent therapeutic efficacy across different compounds [98].

1.7. Therapeutic frameworks: combination strategies and patient stratification

Growing preclinical evidence indicates that coumarins and their synthetic derivatives can enhance antitumor activity through the modulation of autophagy. As autophagy has emerged as a critical determinant of responsiveness to many chemotherapeutic agents—particularly those that induce programmed cell death—its regulation offers a strategic opportunity to improve the therapeutic performance of coumarin-based compounds, especially in combination regimens [99]. Given the dual and highly context-dependent roles of autophagy in cancer progression and treatment response, future investigations should focus on elucidating how coumarins fine-tune autophagic signaling rather than indiscriminately promoting or suppressing this process. Such mechanistic insight could be essential for maximizing their translational relevance.

In parallel, the central involvement of the PI3K/mTOR signaling axis in tumor development and therapeutic resistance further supports the rationale for advancing coumarin-based interventions. Although PI3K/mTOR inhibitors alone have demonstrated limited clinical efficacy, accumulating preclinical data suggest that they can substantially sensitize tumors to other anticancer therapies. Studies in malignancies where coumarins have shown biological activity indicate that combined targeting of PI3K/mTOR signaling may amplify their antitumor effects [[100], [101], [102]]. This approach holds particular promise for patients who exhibit suboptimal responses to standard treatments. Collectively, these observations underscore the importance of mechanism-based patient stratification and rational combination strategies in leveraging coumarins as components of more effective, personalized anticancer therapies.

For instance, 4-methylcoumarin has been shown to enhance the anticancer efficacy of paclitaxel in breast cancer models by promoting apoptosis and modulating autophagic responses. Similarly, combinations of coumarin derivatives with autophagy-modulating agents such as metformin or with PI3K/mTOR inhibitors have demonstrated synergistic effects in preclinical studies, leading to improved cancer cell sensitivity and reduced resistance [24]. These findings support the potential of coumarins as components of rational combination therapies.

1.8. Challenges and opportunities in clinical translation

The obstacles encountered in translating coumarins into clinically viable next-generation anticancer agents simultaneously highlight important opportunities for future investigation. A major challenge lies in defining the pharmacokinetic behavior of coumarin derivatives that modulate autophagy and target the PI3K/mTOR axis, particularly with respect to optimal dosing regimens, treatment duration, and systemic exposure. In addition, potential pharmacodynamic and pharmacokinetic interactions between coumarins and established anticancer therapies warrant careful evaluation. Conventional anticancer treatments frequently impair immune function and are associated with substantial physical and psychological burdens due to complex and sometimes severe adverse effects. Within this context, the adjunctive use of coumarin-rich botanical formulations, such as skullcap extracts, alongside standard anticancer regimens has been proposed as a potentially supportive therapeutic strategy that may help mitigate treatment-related toxicity while preserving anticancer efficacy.

Given the central role of dysregulated autophagy and PI3K/mTOR signaling in tumor initiation, progression, and therapeutic resistance across a wide spectrum of malignancies, strategies that combine coumarin-based autophagy modulators or PI3K/mTOR-targeting agents with existing anticancer therapies are particularly compelling. Moreover, integrating patient stratification based on autophagy-related biomarkers could enable more precise and personalized treatment approaches. Continued advances in understanding coumarin structure–activity relationships, together with the rational design of derivatives with improved safety profiles and a deeper mechanistic insight into autophagy regulation, support an optimistic outlook for the incorporation of coumarins and related scaffolds into future anticancer therapeutic paradigms.

1.9. Future directions and research gaps

Although the role of coumarins in regulating oxidative stress and their implications in disease pathogenesis has been widely discussed, the translation of these insights into clinically effective interventions remains limited. Existing literature has documented the interaction of several coumarin derivatives with the PI3K/mTOR signaling axis; however, a coherent qualitative framework that clarifies whether coumarins predominantly activate or suppress this pathway—and how such modulation ultimately shapes autophagic responses—remains insufficiently developed. Addressing this gap is essential for understanding the therapeutic relevance of coumarin-mediated autophagy regulation. A critical evaluation of both naturally occurring coumarins and recently developed synthetic analogs may accelerate the discovery of novel lead compounds or enable the rational repurposing of established molecules for the management of cancer, including drug-resistant malignancies.

The identification of coumarin-based modulators capable of fine-tuning intracellular signaling pathways represents a key objective for future research. Within the context of PI3K/AKT pathway regulation, the benzopyranone scaffold common to coumarins offers a privileged structural framework for drug development. Rational design of coumarin derivatives that interfere with downstream components of PI3K/mTOR signaling may yield potent small-molecule inhibitors with improved specificity. At the translational level, patient stratification strategies could further enhance therapeutic outcomes by overcoming resistance to autophagy-modulating treatments. Beyond PI3K/mTOR signaling, coumarins are known to influence several additional oncogenic pathways, including MAPK, NF-κB, RGS, GST, and HSF1 networks. Systematic investigation of how these targets intersect with autophagy regulation could be critical for defining the broader impact of coumarins on cellular autophagic flux and autophagy-dependent drug delivery mechanisms.

Key questions that remain to be addressed include: (i) what molecular determinants dictate whether coumarins induce cytoprotective versus cytotoxic autophagy; (ii) how modulation of PI3K/mTOR signaling by coumarins influences long-term therapeutic outcomes; (iii) which biomarkers can reliably predict patient response to coumarin-based therapies; (iv) how pharmacokinetic optimization impacts in vivo efficacy; and (v) whether combination strategies can be systematically tailored to overcome specific resistance mechanisms.

2. Conclusions

This review highlights coumarins as a versatile class of bioactive scaffolds with the capacity to modulate two key regulatory systems in cancer biology: autophagy and the PI3K/mTOR signaling axis. Rather than acting through a single dominant mechanism, coumarins appear to exert context-dependent effects that reflect the intrinsic plasticity of autophagy and the hierarchical nature of PI3K/mTOR-driven oncogenic signaling. This duality—whereby coumarins can either promote cytoprotective autophagy or suppress autophagic flux to sensitize tumor cells to death—suggests that they may function as finely tunable molecular tools rather than nonspecific therapeutic agents. A central insight emerging from the reviewed evidence is that the therapeutic value of coumarins may lie not only in their ability to inhibit PI3K/mTOR signaling, but also in their capacity to modulate autophagic homeostasis in cancer cells that exploit this pathway for survival and drug resistance. By targeting multiple regulatory nodes—including PI3K, Akt, mTORC1/2, ULK1, lysosomal function, and redox-sensitive stress responses—coumarins could potentially interfere with adaptive signaling networks that limit the efficacy of monotherapies. This multi-level activity may be particularly relevant in malignancies characterized by persistent PI3K/mTOR activation and defective autophagic turnover, although further validation is required.

Importantly, the chemical diversity of coumarins provides opportunities for rational structural optimization to align autophagy modulation with specific therapeutic objectives. Advances in synthetic chemistry, hybrid molecule design, and nanoformulation strategies have begun to address limitations related to solubility, bioavailability, and pharmacokinetic stability. When considered alongside emerging insights into structure–activity relationships and toxicity predictors, these developments may support the future development of coumarin-based modulators, although clinical applicability remains to be fully established. From a translational perspective, the potential success of coumarin-centered strategies may depend on mechanism-guided patient stratification and rational combination regimens. Biomarkers such as autophagy status, PI3K/mTOR pathway activation, and stress-response signatures could be useful for patient selection and therapeutic design. Rather than universally inducing or inhibiting autophagy, coumarins may offer the possibility of fine-tuning this process in a tumor- and context-specific manner, potentially improving therapeutic outcomes while limiting toxicity. In summary, coumarins represent a promising and flexible pharmacological platform capable of integrating autophagy regulation with targeted oncogenic pathway modulation. Continued interdisciplinary efforts—bridging medicinal chemistry, systems biology, and translational oncology—may be important for clarifying their therapeutic potential and determining their role in future anticancer strategies.

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Appendix A. Supplementary data

The following is the Supplementary data to this article.