Tokyo stocks opened lower on Wednesday as investors digested the impact of US President Donald Trump's withdrawal from the Iran nuclear deal and fast-moving diplomacy on North Korea.
The benchmark Nikkei 225 index slipped 0.21 percent, or 46.80 points, to 22,461.89 in early trade, while the broader Topix index was down 0.10 percent, or 1.71 percent, at 1,778.11.
The US president rejected appeals by Washington's closest allies and pulled out of a deal he deemed "disastrous".
"The United States will withdraw from the Iran nuclear deal," Trump said in a White House address Tuesday US time, branding the landmark 2015 accord endorsed by Britain, China, Germany, Russia and Barack Obama's administration "defective at its core."
Analysts said North Korean leader Kim Jong Un would be watching closely Trump's decision on the Iran nuclear deal.
Trump "may be using Iran as an example for North Korea to send a message that it will face tough results unless it listens to him," said Kyoko Amemiya, senior market advisor at SBI Securities.
Chinese President Xi Jinping met Kim in China for the second time in six weeks on Tuesday and later spoke with Trump, as the North Korean and US leaders prepare for a historic summit.
Investors were also cautious ahead of Toyota's rare earnings announcement during a trading session, Amemiya said.
"As Toyota president Akio Toyoda will speak after the release of the earnings, investors are keen to know what he will say about mid-term business plans, among other things," she said.
Toyota is due to announce its earnings at 1:25 pm (0425 GMT), while telecoms giant SoftBank will release earnings after the market closes Wednesday.
The dollar fetched 109.04 yen in early Asian trade, up slightly from 108.98 yen in New York late Tuesday.
Takeda was down 2.97 percent at 4,500 yen after it announced a $62.5 billion deal to acquire Irish drug maker Shire.
Toyota was down 0.75 percent at 7,101 yen while SoftBank was down 0.02 percent at 8,487 yen.