Israel struck at the heart of Iran's nuclear, missile and military complex early Friday, in an unprecedented attack that reportedly killed two of Iran's top military commanders and plunges the wider Middle East into dangerous new territory. The strikes on Iran's nuclear program and senior military leaders could be a turning point in the long-running conflict, as Israel braced for a major Iranian retaliation – with the threat of a wider regional war breaking out now a real risk. Later Friday morning, that retaliation appeared to be underway after Israel's military said Iran had launched more than 100 drones toward its territory. All of Israel's aerial defenses had been activated, military spokesperson Effie Defrin said, adding, "we're expecting difficult hours." In a televised address to the nation, Israeli Prime Minister Benjamin Netanyahu said the military operation had "struck at the head of Iran's nuclear weaponization program" and targets included Iran's main enrichment facility in Natanz, Iranian nuclear scientists, and Iran's ballistic missiles program. "Moments ago, Israel launched operation Rising Lion, a targeted military operation to roll back the Iranian threat to Israel's very survival," Netanyahu said in a televised address. "This operation will continue for as many days as it takes to remove this threat." Iran's Supreme Leader Ayatollah Ali Khamenei warned that Israel will face "severe punishment" for the attacks, and confirmed that a number of Iranian commanders and scientists had been killed. Iran's Armed Forces spokesperson said both the US and Israel would "pay dearly." General Hossein Salami, the commander-in-chief of the country's elite Islamic Revolutionary Guard Corps and one of Iran's most powerful figures, was among those killed in the attacks, the IRGC confirmed. Major General Mohammad Bagheri, the chief of staff of Iran's armed forces and the country's highest-ranking military officer, was also killed, according to Iran's state TV IRINN. Iran's former national security chief Ali Shamkhani, a key adviser to Khamenei who served as secretary of the National Security Council for almost a decade, was also killed, IRINN reported. Friday's strikes suggest Netanyahu saw a window of opportunity to meet Israel's longstanding objective of obliterating Iran's nuclear program. Iran is in itsweakest military position in decadesfollowing crippling economic sanctions, previous Israeli strikes on its air defenses and decimation of its most powerful regional proxies, including Hezbollah. A sixth round of nuclear talks between the US and Iran had been scheduled for Sunday, and US officials hadpreviously told CNNthat Israeli strikes on Iran would be a brazen break with President Donald Trump's approach on the Middle East. The United States was not involved in the strikes, US Secretary of State Marco Rubio said, noting that Israel had "advised" the US that it believed the "action was necessary for its self-defense." Earlier, Trumphad warnedof the possibility of "massive conflict" in the Middle East that could take place "soon." Several countries voiced alarm and condemnation at Israel's strikes, with Saudi Arabia's Foreign Ministry saying the attack undermines Iran's "sovereignty and security and constitute a clear violation of international laws and norms," and China's embassy in Iran calling the situation "severe and complex." Ordinary people in Iran faced a long and terrifying night. "People reported the ground shaking, hearing explosions, and jets flying overhead and then waking up, seeing smoke and explosions," Negar Mortazavi, senior fellow at the Center for International Policy, told CNN. Repeated explosions could be heard in the capital Tehran and photos and videos showed what appeared to be apartment buildings damaged or lit up in flames and wounded residents, according to Iranian state media. Iran's airspace has also been closed, its civil aviation authority said. Sirens sounded across Jerusalem before dawn Friday as Israel declared a state of special emergency, closing its airspace, shutting schools and banning social gatherings and non-essential work. Israeli sources told CNN they were bracing for a significant Iranian retaliation, and military chief of staff Lt. Gen. Eyal Zamir said "tens of thousands" of Israeli soldiers were being called up in preparation. An Israeli source told CNN that Israel was planning to carry out multiple rounds of attacks against Iran, saying: "This is not a one-day attack." Analysts and experts have long warned that Israeli strikes on Iran's nuclear capabilities could trigger a massive Iranian retaliation and threaten to tip the region into a full-scale war. And if Israel and Iran become entangled in wider conflict, it could risk drawing in the United States into the fray. The US has long been Israel's closest ally and biggest weapons supplier — there are currently about 40,000 US troops across the Middle East, including nearly 4,000 in Iraq and Syria. Indications of that risk emerged earlier this week as the USordered the departureof non-essential personnel from locations around the Middle East as intelligence warnings increased that an Israeli strike on Iran was imminent. Netanyahu has repeatedly pushed for a military option to stop Iran's nuclear program, and recent US intelligence reports said that Israel was seeking to capitalize on the destruction inflicted after it bombed Iran's missile production facilities and air defenses in October. Experts say an Israeli attack on Iranian nuclear facilities would alsolikely spell the endof Iran's nuclear negotiations with the US. The facility at the heart of Iran's nuclear ambitions was engulfed in flames on Friday, according to social media images geolocated by CNN and Iranian state television. The nuclear complex in Natanz, a city about 250 kilometers (150 miles) south of Tehran, is considered Iran's largest uranium enrichment facility and houses the country's advanced nuclear program. Analysts say the site is used to develop and assemble centrifuges for uranium enrichment, a key technology that turns uranium into nuclear fuel. Friday's strikes came shortly afterTehran saidthat it would ramp up its nuclear activities due to the International Atomic Energy Agency passing a resolution saying that the country was not in compliance with its non-proliferation commitments, senior US officials told CNN. Iran oversees a so-called Axis of Resistance across the region that includes loyal proxies such as Hezbollah in Lebanon and the Houthis in Yemen, as well as various militia groups in Iraq and Syria. Since Israel's war in Gaza began in 2023, attacks by those proxy groups have escalated in solidarity with the Palestinians. Last year Israel and Iran's years-long cold war erupted into the open with a series of missile strikes from both sides. At the time, the US warned Israel not to strike Iran's energy or nuclear infrastructure. And Iran rushed to downplay the strikes, responding with visually powerful but carefully calibrated retaliation that caused limited damage. Friday's operation goes much further than previously seen. CNN's security analyst Beth Sanner said that removing Salami is akin to taking out the US chairman of the joint chiefs of staff: "You can imagine what Americans would do," she said. Iran is now "under existential threat" and as such, the Israelis will be expecting "a massive, much bigger retaliation than what they saw last time," Sanner added. CNN's Oren Liebermann, Jeremy Diamond, Rhea Mogul, Nectar Gan, Jessie Yeung, Todd Symons, Jerome Taylor, Ross Adkin, Juliana Liu, Leila Gharagozlou, Isaac Yee, Teele Rebane, John Liu and Chris Lau contributed reporting. This is a developing story and will be updated. For more CNN news and newsletters create an account atCNN.com