## 1 Introduction  
According to WHO/IARC GLOBOCAN 2022 estimates, the global cancer burden is rising rapidly driven by aging populations, evolving risk factors, and regional disparities. Liver cancer ranks sixth in global incidence and third in mortality and stands out as one of the deadliest malignancies, despite its strong association with largely preventable risk factors (chronic hepatitis B and C, alcohol consumption, and aflatoxin exposure), particularly affecting low-and middle-income countries [1]. Despite significant advancements in therapeutic strategies, including radiotherapy, surgery, immunotherapy and emerging gene therapies, chemotherapy remains a mainstay of cancer treatment, particularly for metastatic or inoperable cases [2]. However, the success of chemotherapy is often hampered by multidrug resistance (MDR), which accounts for over 90% of cancer-related deaths. MDR arises from multiple factors, including tumor-specific mechanisms, host influencesand tumor-host interactions [3]. A critical contributor to MDR is the overexpression of ATP-binding cassette (ABC) transporters, which actively remove chemotherapeutic agents from cells, thereby reducing their intracellular concentration and diminishing their therapeutic efficacy [4; 5]. Notable ABC transporters involved in drug resistance include P-glycoprotein (P-gp/ABCBI), MRP1 (ABCC1), MRP7 (ABCC10), and BCRP (ABCG2) [6]. Doxorubicin, a widely used anthracycline antibiotic derived from _Streptomyces peucetius_, is used either as a single agent or in combination regimens to treat a variety of solid tumors, including hepatocellular carcinoma (HCC) [7; 8]; its cytotoxic effects are mediated through DNA intercalation, topoisomerase II inhibition, and the generation of reactive oxygen species (ROS). ROS production induces oxidative stress, resulting in lipid peroxidation, DNA damage, and protein dysfunction, which trigger apoptosis in cancer cells [9]. However, oxidative stress also harms healthy tissues, particularly the heart, and is a major contributor to dose-limiting cardiotoxicity [10; 11]. Moreover, the development of MDR mechanisms, such as ABC transporter overexpression, significantly compromises doxorubicin's therapeutic potential [12]. In recent years, various strategies have been investigated to overcome MDR, including the use of MDR modulators, nanoparticle-based drug delivery systems, metallic nanoparticles, and RNA interference therapies [13; 14; 15]. Increasing attention has also been given to phytochemicals as adjunctive agents in chemotherapy [16]. These naturally derived compounds have shown promise in enhancing drug accumulation in tumor cells, modulating key signaling pathways and reducing oxidative damage to healthy tissues. Among the most studied classes of phytochemicals are flavonoids, alkaloids, stilbenes (e.g., resveratrol), and curcuminoids (e.g., curcumin), which have demonstrated chemosensitive properties [17; 18]. Polyphenols and flavonoids exert their effects by modulating key signaling pathways such as PI3K/AKT/mTOR, which regulates cell metabolism, and MAPK/ERK1/2, involved in tumor proliferation. Additionally, these compounds inhibit the NF-kB pathway, thereby reducing pro-inflammatory cytokines production and promoting apoptosis in cancer cells [19]. _Leopoldia comosa_ (LC), commonly known as _Muscular comosum_, is an herbaceous plant belonging to the Liliaceae family, native to the Mediterranean region. Its bulbs are a valuable source of bioactive compounds, including phenolic acids, flavonoids, phytosterols, glycosides [20]. Phytosterols exhibit anticancer effects by inhibiting tumor growth, inflammation, and oxidative stress by modulating NF-kB and MAPK/ERK pathways. They also enhance antioxidant defenses and protect mitochondrial function [21]. Glycos play a key role in chemosensitization across different tumor types via multiple mechanisms. Their cytotoxic and antiproliferative effects involve the regulation of the cell cycle and the induction of apoptosis through increased caspase expression [22].